It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this Funding Opportunity Announcement (FOA) is to develop a comprehensive and cohesive understanding of cancer metastasis. Towards this goal, the National Cancer Institute (NCI) will support several U54 Specialized Centers that together will form the Metastasis Research Network (MetNet). Each MetNet Center should propose an overarching scientific theme that will be pursued through two or three inter- and multi-disciplinary basic research projects. The projects should use integrative approaches to elucidate and integrate a mechanistic understanding of the non-linear, dynamic, and emergent processes in metastasis. Overarching themes should encompass the interplay between at least two central components in the metastatic process such as early dissemination, cellular and/or physical microenvironment crosstalk, dormancy, or mechanisms of responses by metastatic cells to therapies.

Research proposed by MetNet Centers is expected to advance our understanding towards a more comprehensive appreciation of metastasis as a whole body, systems-level problem.

Complexity of Metastatic Dissemination. Metastatic cancer accounts for a majority of cancer-associated deaths from solid tumors. Our understanding of the mechanisms associated with metastasis is complicated by the fact that some genetically distinct cancer cells can disseminate early, and, for some, before progression to clinically defined invasive stages of the primary cancer. Dissemination occurs in the context of a multitude of complex reciprocal interactions among the tumor and its soluble and physical microenvironments that can promote dynamic crosstalk between multiple organ systems. Despite increased understanding of many of the individual steps in metastasis, less is known about how each step is influenced by or influences distant tissues and the whole organism. Dissemination can also occur non-linearly, via multiple concurrent, partially overlapping routes that require the acquisition of cell autonomous and microenvironment-mediated metastasis-promoting phenotypes. Because the molecular requirements are distinct for growth in different organs and environments, defining such phenotypes is challenging. However, use of integrative approaches that incorporate the host micro- and macroenvironment, immune-mediated events, and crosstalk among the primary tumor, pre-metastatic and metastatic sites can aid in shedding light on the complexity and dynamic nature of metastasis.

Understanding the Spectrum of the Metastatic Process. In general, metastasis research has often focused on discrete elements of the metastatic process, such as the acquisition of an invasive and migratory phenotype with experimental systems mimicking intravasation and extravasation using advanced stage tumor models or accelerated metastasis models in murine systems. Although these systems often use human cells, the extent to which these models reflect the mechanisms of metastasis in patients is unclear. Improving physiologically relevant models that capture the entire metastatic process and further developing probes to track and monitor the in vivo dynamics of metastatic cell states would help facilitate understanding of the spectrum of metastasis. In patients with cancer, metastatic cells lie dormant or quiescent at the secondary site for weeks, months, or years, only to recoup proliferative ability and develop overt metastases that appear later in clinical progression and/or after primary treatment. The molecular, cellular, and tissue-level mechanisms that contribute to early dissemination, dormancy, and eventual growth of detectable metastatic lesions are not well understood and definitive in vivo measures of early metastasis and metastatic dormancy are needed to continue to propel the field to the next level. Also, it is of high clinical importance that we improve our understanding of the mechanisms underlying responses of metastatic cells to cancer therapy, which depend not only on the genetics of the metastatic lesion, but also on the physical, chemical, and cellular microenvironment of the metastatic site.

Metastasis as a whole-body, systems-level challenge. The cooperation between the entire system or organism and multiple cellular phenotypes leading to metastasis and supporting metastatic outgrowth makes metastasis research a whole-body, systems-level/physiology challenge. Therefore, undertaking metastasis research using dynamic, holistic systems-level approaches taking an integrated perspective that considers the whole organism could generate mechanistic models that encompass dynamic biological scales, and provide opportunities to derive a more comprehensive picture of metastasis. Such approaches incorporating the complexities associated with the dissemination of cancer cells from a primary lesion to establishment and growth at a distal site will help identify common/unique components across cancers and tissues, and identify potential dependencies that may be vulnerable to perturbation or intervention.

Overarching goal of MetNet: The MetNet will create a nexus of centers comprised of multi-investigator teams working in distinct but functionally related areas of metastasis. Each center should use multi-and/or inter-disciplinary approaches drawn from, but not limited to, cancer biology, cell biology, physiology, bioengineering, physics, systems biology, and/or bioinformatics. MetNet Centers must incorporate robust experimental approaches and analytical technologies that bridge multiple molecular, cellular, and organ-level processes towards a systems-level view addressing critical questions related to the non-linear, dynamic and emergent processes of metastasis. MetNet Centers should place emphasis on understanding two or more core components:

1. The likelihood, timing, and frequency of early dissemination;

2. The interaction and crosstalk of metastatic cells with the immune and nervous systems, vasculature, and the physical microenvironment;

3. The acquisition of, maintenance of, or emergence from metastatic dormancy; and

4. The mechanisms of response of metastatic cells, including those that are dormant, to therapies.

This FOA invites applications in which each MetNet Center identifies an overarching theme that serves to integrate the individual center projects towards understanding the interplay and crosstalk between two or more of the bulleted topics above and ensures that the results of the research are greater than the sum of its parts.

Examples of individual research center project topics that could be integrated towards a systems-level understanding of metastasis include, but are not limited to:

• Development of clinically relevant experimental and/or in silico models that concurrently address multiple dynamic and plastic states in the metastatic process, including the role of the macroenvironment, i.e., host physiology or the larger-scale and long-term environment and conditions that affect an organism;
• Development of tools to identify and track metastatic cells in vivo or in engineered metastasis models, including metastatic dormant cells or other micro- or macro- metastatic lesions;
• Determination of cell intrinsic and/or microenvironmental factors that facilitate early tumor cell dissemination including angiogenic, immunogenic, neurogenic and/or other stromal cells and structural proteins;
• Characterization of molecular and phenotypic signatures that define the dormant state in various secondary organs or metastatic sites and how those molecules and phenotypes act in concert with the mechanisms underlying metastatic dormancy;
• Determination of cell intrinsic and/or microenvironmental factors that support maintenance of a dormant state, dynamic phenotypic switching, and/or exit from dormancy;
• Examination of the role of stem-like or developmental cellular features that facilitate early dissemination of tumor cells or emergence from the dormant state;
• Determination of the mechanisms associated with responses of therapy on promotion, maintenance, or preventing emergence from a dormant state;
• Quantification of the dynamics of tumor-micro/macroenvironment interactions, including local or systemic tumor cell interactions with distant cells, tissues, and/or organs.

MetNet Research Center Expertise: This FOA requires applicants assemble collaborating teams with principal expertise in metastasis. The Center should consist of a research team of investigators with complementary expertise organized around a metastasis research theme, such as those described in the Research Objectives section above. Expertise could involve basic cancer biology, cell biology, engineering, physics, physiology, development or application of novel technologies and approaches to data integration. Consequently, the MetNet Centers will require leadership having the ability to manage and understand the various approaches needed.

Each Center will consist of the following components:

1. Research Projects At the foundation of each MetNet Center will be high impact research projects that support the overall research theme. MetNet Centers will consist of a minimum of two Research Projects that integrate into the overall research theme.

2. Administrative Core Each MetNet Center will have their own Administrative Core that will guide the organizing framework and connect the individual Center to the broader MetNet community and the NCI. Expectations for the members of the Administrative Core include:

• Serving as the primary contacts for internal logistical and organizational aspects of the Center, including non-scientific activities
• Serving as the primary contact for external interactions with the other MetNet Centers, the NCI, and the metastasis research community.
• Managing solicitation, review, and funding of Center pilot projects.
• Identifying and specifying a project manager and a data manager. These designated managers will be responsible for facilitating interactions and ensuring data, resources, and tools are submitted to the appropriate NIH resources.
• Engaging a patient advocate to participate in Center activities, including but not limited to, participation in steering committee and Annual Meetings and review and selection of pilot projects.

3. Shared Research Core (optional) Although not required, a Shared Resource Core may be established to provide expertise and resources (e.g., imaging, models, biological specimens, pathology, computational modeling and analyses).

Overall Network organization: The overall network will consist of both the centers funded through this initiative and pilot projects initiated in the out years (2nd through 5th years of funding). The MetNet will function as a collaborative network encouraging individual Centers to share resources and model systems, cross validate ideas and observations, and integrate data.

Governance of the MetNet: The MetNet Centers will be governed by the MetNet Steering Committee. Details on the composition and functions of the MetNet Steering Committee are provided in Section VI, Terms and Conditions of Cooperative Agreement.

Evaluation of the Program: As the efficiency of the funded research is an important priority for NCI, MetNet Centers will be required to participate in an external evaluation process of the MetNet program coordinated by NCI Program staff (see Section VI, Terms and Conditions of Cooperative Agreement.)

The following types of projects are non-responsive for this FOA, and applications meeting these criteria will not be reviewed:

• Applications that do not focus on cancer metastasis or those that focus on only one element or step in the metastatic process;
• Applications that propose population-level epidemiology studies or clinical trials.

IMPORTANT NOTE: Applicants uncertain as to whether their intended project meets the requirements of this FOA are encouraged to contact the Scientific/Research Contact listed below in Section VII.

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• o   Hispanic-serving Institutions
• o   Historically Black Colleges and Universities (HBCUs)
• o   Tribally Controlled Colleges and Universities (TCCUs)
• o   Alaska Native and Native Hawaiian Serving Institutions
• o   Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Joanna Watson, PhD
Division of Cancer Biology
National Cancer Institute (NCI)
Telephone: 240-276-6206
Email: [email protected]

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	12
Admin Core	6
Project (use for each Research Project)	12
Core (use for each Shared Resource)	6

Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

• Overall: required
• Administrative Core: required, maximum of 1
• Research Projects: required, minimum of 2 and maximum of 3
• Shared Resource Core(s): optional, maximum of 2

When preparing your application, use Component Type Overall .

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete entire form.

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Follow standard instructions.

Enter primary site only.

Project Summary /Abstract: Succinctly describe the overall research theme of the MetNet Center and how the individual Research Projects contribute to an integrated, systems-level understanding of metastasis.

Project Narrative: State how the outcomes of the MetNet Center will contribute to a more comprehensive picture of metastasis, and the potential impact on public health.

Facilities & Other Resources: In addition to the information required in the standard instructions, highlight available facilities and/or services dedicated specifically to metastasis research (e.g., microscopy facilities, comparative medicine cores, etc.). Indicate on what basis these resources will be available to other MetNet investigators (e.g., in-lab, freely available, fee-for-service, etc.).

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

Introduction to Application: For Resubmission applications, an Introduction to Application is required in the Overall component.

Specific Aims: State the overall vision and goals for the MetNet Center. The Specific Aims should be overarching, at a high level, and distinct from the aims of the individual components. It should be clear how the aims will lead to a more comprehensive picture of the non-linear, dynamic, and emergent processes of metastasis.

Research Strategy: Present a concise overall vision and plan for the proposed MetNet Center. The vision should focus on the plans for the funding period of the Center and how the work will contribute to a more comprehensive understanding of metastasis. This section should describe the fundamental question(s) in metastasis research that will be addressed by the Center and how they integrate to form an overall central research theme centered on at least two of the identified elements: 1) the likelihood, timing, and frequency of early dissemination; 2) interaction and crosstalk of metastatic cells with the immune and nervous systems, vasculature, and physical microenvironment; 3) the acquisition of, maintenance of, or emergence from metastatic dormancy; and 4) the mechanisms of response of metastatic cells, including those that are dormant, to therapies. Items to be addressed include:

• Research Theme. Define the overall central research theme of the MetNet Center. Provide a brief background and rationale for this selection and outline the significance of research in the selected area.
• Research Center Organization. Provide a concise description of the structure of the Research Center and explain the following aspects: (1) how the skills of individual team members will translate into the collective ability of the center to accomplish the stated goals for interdisciplinary metastasis research and other activities; (2) your vision of the integration of the components into a Research Center as an entity that would be greater than the sum of its parts in terms of ability to advance fundamental question(s) in metastasis research and, (3) how the components of the Research Center, including key personnel, will interact to realize this vision.
• Research Projects. In a brief overview, outline the rationale for each project and the expected gains in terms of new knowledge advancing the research theme of the Center.
• Shared Resource Core(s) (If applicable). Briefly explain the need for any Shared Resource Core(s), indicating the specific Research Projects that will be supported by each Core. It is generally expected that a Shared Resources Core will support at least two research projects.
• Patient Advocacy. As part of the Administrative Core functions, each MetNet Center is encouraged to engage patient advocate(s). Briefly state the plans for such patient advocate engagement with the Research Center's program. Further details regarding implementation of patient advocates should be included in the Administrative Core.

Letters of Support: In addition to standard items, applicants must provide letters from the respective leadership official(s) in the lead institution(s) documenting specific institutional commitments to the proposed center.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any 1 year, should address a Data Sharing Plan.
• The Data Sharing Plan should be provided only under the Overall component section, but it should cover all the activities of the Center.
• Each MetNet Center is expected to have a designated data manager because in many cases it is expected that data quality control and wrangling will be a major activity within the MetNet Center in preparation to share high-quality data with the scientific community. Within the data sharing plan, applicants should address what types of data will be generated, and who will be responsible for quality control, wrangling, and deposition of those data to NIH resources. A budget that accounts for data sharing activities through the appointment of a specific, qualified data manager is expected.
• The Data manager will be expected to sit on the Resource and Data Sharing Working Group of the MetNet. This working group will be responsible for discussions regarding standard metadata fields, determine whether there will be pre-publication of data sharing across the MetNet, create standard operating procedures for MetNet data upload in conjunction with the different NCI Cancer Research Data Commons, and lead the conversations about data quality control, cross validation, etc.
• A Resource Sharing Plan should also describe the models that are expected to be generated and shared, consistent with achieving the goals of the MetNet.
• Data, software, and models from this FOA are expected to be shared in an easily accessible format with the scientific community to increase the value of the significant public investment. Note that the NCI Program staff may negotiate modifications to these plans prior to funding. All applicants are expected to abide by the NIH and NCI data sharing policies. For example, see NIH Genomic Data Sharing Policy for more information. (see Section VI: Terms and Conditions of Cooperative Agreement).

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

All instructions in the SF424 (R&R) Application Guide must be followed

All instructions in the SF424 (R&R) Application Guide must be followed.

When preparing your application, use Component Type Admin Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The MetNet Center PD/PI (contact PD/PI for applications with multiple PDs/PIs) must serve as the Administrative Core leader.
• The Administrative Core must designate a qualified Center Administrator to manage the day-to-day operations with responsibility for the administrative, budgetary, and operational aspects of the Center. For the Center Administrator, in the additional Senior/Key Profiles section, use Project Role of 'Other (Specify)' and provide the role under 'Other Project Role Category' as 'Center Administrator'.
• The Administrative Core must designate a qualified Center Administrator to serve as the Center Data manager. The Center Data manager will be a member of the Resource and Data Sharing Working Group and responsible for all deposition into appropriate repositories and sharing of data across in a timely manner. More information regarding the needed duties of the Data manager are listed above in the Resource and Data Sharing Plan associated with the Overall section of the application.

Budget forms appropriate for the specific component will be included in the application package.

Leadership Effort Commitment: The MetNet Center contact PD/PI must commit and maintain through the life of the award a minimum of 2.4 calendar-month of effort if the Center contact PD/PI is also an individual Project leader. The required levels of effort may reflect an aggregate of the effort for the entire MetNet (listed here under Administrative Core) and the efforts for other MetNet components, as applicable.

Center Administrator. Based on the complexity of the MetNet Center, applicants are expected to propose and budget for a Center Administrator to manage day-to-day operations, and for a Center Data manager. The Data manager will be expected to sit on the Resource and Data Sharing Working Group of the MetNet. This working group will be responsible for discussions regarding standard metadata fields, determine whether there will be pre-publication of data sharing across the MetNet, create SOPs for MetNet data upload in conjunction with the different NCI Cancer Research Data Commons, and lead the conversations about data quality control, cross validation, etc.

Funds for Intra-Center Pilot Projects: A minimum of $50,000 per year (direct costs) must be allocated to a fund for support of post-award pilot projects hosted within each Center for years 2-5.

Travel Funds: The budget should include funds to support travel for Center and Network activities, including but not limited to supporting the travel and participation of PD(s)/PI(s) and other MetNet Center members to the annual MetNet Investigators Meeting and annual site visits.

Other: Funds (including travel if appropriate) may be allocated for expenses related to the formation of an External Advisory Committee and for any patient advocacy-related activities. It is expected that funds will be allocated for open-access publishing.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Outline Specific Aims for the Administrative Core.

Research Strategy: The Administrative Core is expected to have appropriate and effective administrative and organizational capabilities to: support metastasis research; foster synergy and integration of the Research Center; engage with the metastatic cancer patient advocacy community; and support planning and evaluation activities. Applications must describe the structure of the Administrative Core using the following subsections (instead of the standard sub-sections):

In lieu of the standard Research Strategy subsection (Significance, Innovation, Approach) use the sub-sections defined below to present a concise overall vision and plan for the proposed MetNet Center:

Sub-section A.

Center logistics and communication: Describe the strategies for communication across the Research Center leadership (multiple PD(s)/PI(s)) and key Research Center investigators, and between project teams consisting of multidisciplinary investigators. Describe the Center's strategy to work and communicate with the other Centers that will be part of the MetNet, and with the NCI. State who will be the lead for each level of communication. Provide a strategy for integration of new and early-stage investigators into the Research Center structure and environment.

Sub-section B.

Intra-Center Pilot Projects: Describe how the Administrative Core will coordinate the solicitation, evaluation, and support of 1-year intra-Center pilot projects in years 2-5. Indicate how pilot projects will be solicited and prioritized to ensure that they address and advance the overall research theme of the Research Center. Outline the evaluation process of the proposed pilot project, including specific details, e.g., what body/panel will review the application and who will be in charge of final project approval. Mention any anticipated follow up after a pilot project is selected for execution such as communicating details about funded pilot projects to NCI program staff, evaluation of project progress, options to terminate or change direction for non-performing projects, etc. Note: Do NOT propose any pilot projects in the application. However, the description may signal anticipated general directions and/or circumstances when pilot projects may be deemed particularly needed (e.g., the emergence of new knowledge or technology that creates a new opportunity to advance the theme of the Research Center but not covered by the full research projects).

Sub-section C.

External Advisory Committee and Patient-Advocate involvement: Each awarded MetNet Center will recruit external experts (from outside of the Center) who will serve as scientific advisors to the MetNet Center leadership. Describe the anticipated general composition of the external advisory panel, the range of expertise to be sought, and how the panel might be expected to contribute to the Center's activities. It is important that no potential External Advisory Committee members be contacted or recruited before the review of the application has been completed.

Sub-section D.

Patient-Advocate Involvement: As part of the Administrative Core functions, each MetNet Center is encouraged to engage patient advocate(s) to help provide perspectives and frame questions. Describe efforts to encourage patient-advocate participation in Center activities. Such activities could include, but are not limited to, participation in steering committee discussions, attendance at Annual meetings, activities related to teaching and/or improving basic science communication, and assistance with review and selection of pilot projects.

Letters of Support: Include letters of support as appropriate.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application in ASSIST, use Component Type Project.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project starting with "Project 1:", "Project 2:", etc.
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Projects)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Summary/Abstract: Provide an abstract/summary for the proposed Research Project, including how it fits within the research theme of the MetNet Center.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Research Projects)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• The Project Lead must dedicate at least 1.8 calendar months effort to the project for the life of the award. If the project has multiple leads, then each lead must dedicate at least 1.2 calendar months effort to the project for the life of the award.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• For projects with multiple leads, in the Project Director/Principal Investigator section of the form, use Project Role of Other (Specify) and designate the role under 'Other Project Role Category' as Project Co-Lead and provide a valid eRA Commons ID in the Credential field. For other co-leaders, in the additional Senior/Key Profiles section, use Project Role of Other (Specify) and provide the role under 'Other Project Role Category' as Project Co-Lead and provide a valid eRA Commons ID in the Credential field.

Budget forms appropriate for the specific component will be included in the application package. The Project Lead must dedicate 1.8 calendar months effort to the project for the life of the award. If the project has multiple leads, then each lead must dedicate at least 1.2 calendar months effort to the project for the life of the award.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each project.

Specific Aims: State the specific aims of the Research Project and provide a rationale and description of how they fit into the overall research theme of the Research Center.

Research Strategy: The Research Projects constitute the most important activities of the Research Center and should focus on robust approaches that consider and integrate the entirety of the system to generate mechanistic models to the metastasis research questions related to the theme of the Research Center.

Applicants should use the standard structure of the Research Strategy section (i.e., sub-sections Significance, Innovation, and Approach).

Within these sub-sections, address the following additional aspects of each project:

• Provide a concise description of how the Project is integrated within the Center and contributes to the MetNet Center's overall research theme.
• State the multidisciplinary aspects of the Research Project and how it benefits from the unique scientific expertise of Research Center personnel.
• Indicate how the project team will take advantage of the Research Center infrastructure to allow for new approaches or perspectives to be quickly implemented or tested to provide a more comprehensive picture of metastasis.
• If the Research Project will use the Shared Resource Core(s), describe how the Core(s) capabilities impact the proposed project.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Resource Sharing Plans should only be included in the Overall component.

Appendix: Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving human subjects research and/or NIH-defined clinical research follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Shared Resource Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Core(s) starting with: "Core 1:","Core 2:"
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Shared Resource Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Shared Resource Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Shared Resource Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Shared Resource Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• For Cores with multiple leads, in the Project Director/Principal Investigator section of the form, use Project Role of Other (Specify) and designate the role under 'Other Project Role Category' as 'Core Co-Lead' and provide a valid eRA Commons ID in the Credential field. For other co-leaders, in the additional Senior/Key Profiles section, use Project Role of 'Other (Specify) and designate the role under 'Other Project Role Category' as 'Core Co-Lead' and provide a valid eRA Commons ID in the Credential field.

Budget (Shared Resource Core)

Budget forms appropriate for the specific component will be included in the application package.

The Core Lead(s) must each commit and maintain through the life of the award a minimum of 0.6 calendar-months per year of effort. If there are multiple Core Leads, it is not necessary that each commit equal effort to the project.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Shared Resource Core)

Introduction to Application: For Resubmission applications (those that have previously submitted to this FOA), an Introduction to Application is allowed for each core.

Specific Aims: In addition to outlining the specific aims of the Shared Resource Core, list which projects will be supported by the Shared Resource Core.

Research Strategy: The Shared Resource Cores may be physical or virtual infrastructures (e.g. imaging, or cloud-based computing or storage) providing a biological, pathological, computational or engineering resource that supports other Center components in their activities. Each Shared Resource Core is expected to support at least two Research Projects and the services and resources provided to other Research Center components should be clearly defined. Issues to be addressed include, but are not limited to:

• Value of the Core services to the Research Center and Research Projects;
• Integration between the Core and Research Projects;
• Procedures for selecting Research Projects to use the Core, including allocating resources, cost effectiveness, and increased efficiency; and
• Quality control measures.

Any proposed new shared resources must not duplicate analogous resources already established in the applicant institutions. If existing cores and resources are to be used, then funding to augment such existing resources may be requested. Description of how work related to the Center will be prioritized within such a core must be provided.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Resource Sharing Plans should only be included in the Overall component.

Appendix: Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Shared Resource Core)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Shared Resource Core)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management (SAM). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of the NCI , NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this FOA, note the following:

Reviewers will provide an overall Impact Score for the entire MetNet Center and adjectival merit ratings (numerical score) for individual components (Projects, Administrative Core, and other Shared Research Core(s)]. Reviewers will be assigned to evaluate the entire application. Individual components of the application can be rated numerically.

For the evaluation of the MetNet Center application, the Research Projects will be assessed as the scientific basis of each Center and its most important components, with additional components enhancing and integrating the overall research program. The overall Impact Score will reflect the synergy and integration provided by inclusion of each MetNet Center component.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the MetNet Center to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the Center proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the MetNet Center address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the proposed MetNet Center are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

• Specific to this FOA: How well does the research theme of the proposed Research Center address fundamental questions in metastasis research?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the MetNet Center? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA: How well does the MetNet Center leadership team have the appropriate breadth and balance of expertise in metastasis? How well do the Research Center Project Leads and other key personnel have the necessary specialized research expertise? How well does the expertise of the key personnel complement each other? How well do the proposed interactions and collaborations between the MetNet Center PD(s)/PI(s), Project Leads, and other key personnel unite the components and advance the science of the Center?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the MetNet Center? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the MetNet Center involves human subjects and/or NIH-defined clinical research, are the plans to address:

1) the protection of human subjects from research risks, and

2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA: How well does the overall research theme of the Research Center integrate perspectives and robust multipronged approaches that encompass the dynamics and multiple biological scales to derive a more cohesive picture of metastasis? How well does the proposed research approach consider non-linear, dynamic, and emergent processes of metastasis?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Specific to this FOA: How well does the Research Center environment promote collaborations and transdisciplinary research?

As applicable for the MetNet Center proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Integration

• Will the proposed Center be a truly integrated entity, rather than a collection of unrelated research projects and support services? How well does the MetNet Center organization promote scientific and administrative integration, synergy and a cohesive research program? How will the applicants collaborate and share models, software, and other resources within the MetNet Center and across the Network? Do the overall research theme and the proposed activities (Cores, Research Projects) require a Center-based research structure for success? How well integrated are the individual components to form a MetNet Research Center that is greater than the sum of its parts?

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. A project does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a Research Project that by its nature is not innovative may be essential to advance a field.

Impact Score

• Reviewers will provide an impact score to reflect their assessment of the likelihood for the research project to exert a sustained, powerful influence on the research field, in consideration of the following review criteria.

Significance

• Does the Project address a fundamental question(s) relevant to metastasis research that considers the non-linear, dynamic, and emergent processes in metastasis? Is the prior research that serves as the key support for the proposed project rigorous? Will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? How well does the Project advance the overall research theme of the Research Center?

Investigator(s)

• Are the Project Lead(s), collaborators, and other researchers well suited to the Project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If the project is collaborative or has multi-Project Leads, do the investigators have complementary and integrated expertise? Does the Project optimally use the combined multi-disciplined research expertise? How does the Project benefit from the unique scientific expertise of the Research Center?

Innovation

• Does the project challenge and seek to shift current research or clinical practice paradigms by applying approaches that consider the entirety of the system and perspectives to metastasis research? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, models, or interventions proposed?

Approach

• Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Project? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility, and will particularly risky aspects be managed? How well does the Project integrate perspectives and approaches to address the metastasis research question(s)? Does the Project approach integrate into the research theme of the Research Center?

  If the Project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

• How well does the proposed research use multi-pronged integrative approaches to encompass the dynamics and multiple biological scales to derive a more cohesive picture of metastasis? How well does the proposed research approach consider non-linear, dynamic, and emergent processes of metastasis?

Environment

• How well does the Project environment promote collaborations and interdisciplinary research? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? How will the project benefit from unique features of the scientific environment of the Center, subject populations, or collaborative arrangements?

• Reviewers will provide only one score/adjectival rating for the Administrative Core (criterion scoring is not used for this component). Reviewers will consider the following criteria to determine an impact score:
• Does the MetNet Research Center Administrative Core team have the appropriate expertise to manage logistics and communication within the Research Center?
• Is the plan for intra-Center pilot project solicitation, review, and funding fair and sensible?
• Are the anticipated scope of expertise and processes for oversight and strategic planning of an External Advisory Committee to be formed appropriate for the needs of the proposed Research Center?
• Is the plan for patient advocacy involvement reasonable and achievable?

• Reviewers will provide only one score/adjectival rating for the Shared Resource Cores (criterion scoring is not used for this component). Reviewers will consider the following criteria to determine an impact score:
• How well matched is the proposed Shared Resource Core to the needs of the overall Research Center? Are the services of the Shared Resource Core essential to the goals of more than one Research Project?
• Are the qualifications, experience, and effort commitment of the Shared Resources Core Director(s) and other key personnel adequate and appropriate for providing the proposed facilities or services?
• Will the proposed Shared Resource Core provide cost effective services to the Research Center, prevent duplication, and/or increase efficiency?
• What is the overall quality level of the proposed Core services and technologies and the rigor of processes for quality control/quality assurance?

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed MetNet Center involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable.

Not Applicable.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan .

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NCI in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex.  This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency.  Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
• HHS funded health and education programs must be administered in an environment free of sexual harassment.  Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws.  Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions.  Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.  

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. 

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Overseeing the scientific research in the Research Center, analyzing and interpreting research data, reporting results to the scientific community, and disseminating approaches, methods, models, software, and tools broadly.
• Agreeing to be an active participant in the MetNet, including attending the Annual Investigators Meeting, participating in other network sponsored meetings and workshops, and participating in collaborative activities.
• Promoting trans-MetNet and external collaborations to advance metastasis research.
• Serving on the MetNet Steering Committee. The MetNet Center PD(s)/PI(s) (contact PD/PI for applications with multiple PD(s)/PI(s)) are required to serve as members of the Steering Committee.
• Abiding by the governance of the MetNet and all program policies agreed upon by the MetNet Steering Committee and approved by NCI Program Officials to the extent consistent with the applicable rules and regulations.
• Reporting progress to the NCI Program Officials on all MetNet Center research and activities annually. The PD(s)/PI(s) may be expected to provide additional information, outside the scope of the standard reporting requirement, as needed and requested by program staff members on a semi-annual basis.
• Active participation by the designated Data manager, who will be expected to sit on a Resource and Data Sharing working group. This working group will be responsible for discussions regarding standard metadata fields, determine whether there will be pre-publication of data sharing across the MetNet, create SOPs for MetNet data upload in conjunction with the different NCI Cancer Research Data Commons, and lead the conversations about data quality control, cross validation, etc.
• Ensuring that data are deposited in a timely manner in appropriate publicly available databases, and that models, software, and other tools and resources developed as part of this Research Center are made publicly available according to MetNet policies.
• Ensuring that results of the Research Projects are published in a timely manner.
• Being prepared for the annual site visits of NCI Program staff members and participation in the NCI-coordinated evaluation of the MetNet program. The Administrative Core should coordinate participation in Research Center program evaluation activities, including progress reports, site visits, and formation of an external advisory committee.
• Engaging a patient advocate or advocates in Center activities.
• Organizing scientific working groups to facilitate collaborative pilot projects and validation of experimental concepts and observations.
• Notifying NCI Program staff members about intra-Research Center pilot projects (those funded through restricted funds in the Administrative Core) selected for implementation (with information on the scope of these projects and how they can contribute to the overall research theme of the Center).

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies. Participating MetNet Research Center members are also encouraged to organize and participate in other Network meetings and workshops, organize collaborative activities, and promote Trans-Network collaborations, and organize and participate in scientific and programmatic working groups.

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

One or more designated NCI Program staff members will have substantial involvement as Project Scientists in the awards under this FOA. The specific roles of the substantially involved NCI staff members include the following activities:

• Serving as voting members of the MetNet Steering Committee;
• Serving as resource for the MetNet in making them aware of other ongoing NCI activities that may be relevant to the study or goals of the MetNet;
• Serving as a member of the Resource and Data sharing working group;
• Assisting the Steering Committee, and individual U54 awardees in avoiding unwarranted duplications of effort across the MetNet;
• Facilitating collaborative research efforts that involve multiple MetNet Research Centers.
• Assisting the awardees as a resource in facilitating their broader interactions with other NCI and NIH programs to disseminate results, tools, and models from the MetNet and take advantage of existing NIH/NCI resources and infrastructures;
• Evaluating the effectiveness and facilitating network-wide adoption of resource practices;
• Monitoring the operations of the MetNet awardees and making recommendations on overall project directions and allocations of MetNet Center funds;
• Reviewing the progress of the MetNet awardees, conducting periodic site visits, and taking other actions as needed;
• Participating in organizing annual MetNet meetings, specialized workshops, and webinars of the consortium;
• Additionally, an agency program official or IC program director will be responsible for the standard scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

The MetNet will have a Steering Committee as a governing body. The MetNet Steering Committee will consist of:

• The contact PD/PI (for MetNet Research Centers with multiple PD(s)/PI(s)) from each awarded MetNet Research Center;
• Patient advocates;
• NCI Project Scientists.

Each member of the Steering Committee will have one vote. NCI Project Scientists have one combined vote. Additional NIH/NCI program staff and other government staff may participate in MetNet Steering Committee meetings as non-voting members. The structure is designed to allow awarded investigators and NCI staff to work together to facilitate trans-MetNet activities based on synergistic expertise and projects.

Two PD(s)/PI(s), representing two different MetNet awards, will be selected to serve as chairs of the Steering Committee starting at the first meeting of the Steering Committee following award issuance. All MetNet Steering Committee decisions and recommendations that require voting will be based on a majority vote.

The Steering Committee may have additional non-voting members.

The MetNet Steering Committee will meet annually at the MetNet Annual Investigator Meeting and as needed.

The MetNet Steering Committee will:

• Identify scientific and policy issues that need to be, or can benefit by being, addressed at the Network level and develop recommendations to NIH/NCI Program Officials for addressing such issues;
• Review progress of the MetNet toward meeting the overall Network goals;
• Ensure that all MetNet administrative and data managers actively engage with the network;
• Coordinate dissemination of Network output to the broader cancer research community;
• Review the potential of Shared Resource Core(s) at individual Research Centers to serve the needs of other Research Centers or Research Projects and develop appropriate policies for such activities;
• Ensure that the Network takes advantage of existing NCI and NIH resources and programs;
• Establish, as necessary, subcommittees to ensure progress of the individual Centers, Projects, and the Network.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Joanna M. Watson, PhD
National Cancer Institute (NCI)
Telephone: 240-276-6206
Email: [email protected]

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: [email protected]

Amy Bartosch
National Cancer Institute (NCI)
Telephone: 240-276-6375
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.