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Issued by

National Cancer Institute (NCI)

Purpose

The purpose of this Notice of Special Interest (NOSI) is to stimulate research on the role of RNA modifications in the area of cancer biology. Despite the recognition that RNA modifications and editing exert substantial impact on gene expression and function, there are a lack of mechanistic insights into the dynamic regulation of RNA modifications and how their de-regulation drives cancer formation. A better understanding of the extent, diversity and crosstalk between different types of RNA modification, and the elucidation of the molecular players that read and interpret the modification code are needed to reveal the mechanisms of RNA modifications that underly cancer formation and the cancer phenotype.

Background

RNA Modifications: The conversion from genotype to phenotype proceeds through transcription of RNA molecules that undergo co- and post-transcriptional processing (splicing, capping, polyadenylation) before exerting their functions as RNAs or as proteins after translation. An additional layer of genetic information has been emerging with the widespread detection of chemical modifications in RNA molecules. To date, more than 170 types of RNA modifications have been reported, including N⁶-adenosine methylation (m⁶A), adenosine to inosine (A-to-I) deamination, cytosine to uracil (C-to-U) deamination, N¹-adenosine methylation (m¹A), 5-cytosine methylation (5mC), pseudouridylation (ψ), and ribose 2’O-methylation. There is a growing list of RNA modifications found in coding and non-coding RNAs that impact their biological functions as they often lead to alterations in RNA stability, folding, interaction, translation, localization, and subsequent processing. However, insights into the molecular machineries that deposit and remove, as well as recognize and interpret these modifications within the cell are available for only a few modifications. And even for those types of modifications where writers, erasers and readers have been identified, such as N⁶-adenosine methylation, little is known about their regulation, their cooperation or competition with other RNA modification and processing events, and how they become de-regulated in disease.

Since some chemical moieties can be added and removed in a dynamic fashion on short time scales, approaches for the quantitative, cell- and transcript-specific mapping of RNA modifications are critical. Some types of RNA modification alter base-pairing behavior (A-to-I and C-to-U base-modification editing) or chemical properties (pseudouridylation, 5mC) of the RNA molecule and can thus be directly detected and mapped through sequencing-based approaches. For others, such as m6A, detection to date relies on indirect methodologies such as immunoprecipitation of modified RNAs with modification-specific antibodies or bulk chromatography and mass spectroscopic approaches. The majority of RNA modifications are difficult to detect since methodologies for transcriptome-wide mapping and quantitative determination of modification rates at the single nucleotide level are not available. This substantially impedes the investigation of their functional roles and disease relevance of these RNA modifications.

RNA Modifications in Cancer: There is emerging evidence that RNA species become hyper-, hypo- or mis-modified in cancer, and that the over- or under-expression, mutation, or deletion of molecular players in RNA modification can be linked to the cancer phenotype. For example, aberrant deposition, removal, and recognition of N⁶-adenosine methylation (m6A), the most predominant type of RNA modification in mammals, is associated with diverse human cancers. In acute myeloid leukemia (AML), dysregulation of m6A by aberrant expression of either the FTO demethylase or the METTL3 methyltransferase can lead to differentiation blockage and leukemogenesis. The proteins may regulate distinct sets of targets and thereby display oncogenic roles in the same cancer cell context. In glioblastoma (GBM), the METTL3 methylase has been shown to function as a tumor suppressor, while the demethylase FTO and the m6A reader ALKBH5 are associated with poor clinical outcome and enriched in glioma stem cells. The levels of m6A within mRNAs of hepatocellular carcinoma tissues were found to be decreased due to the downregulation of the methylase complex, which was associated with metastasis and worse prognosis. Overall, the m6A machinery of writers, erasers, and readers is deregulated in a range of human cancers and functions as either oncogenes or tumor suppressors, suggesting a substantial interaction between m6A modification and the development of human cancers. Nonetheless, mechanistic insights into the molecular events that drive these changes during cancer formation are largely lacking.

The A-to-I RNA editing of both coding and non-coding RNAs constitutes another prevalent type of modification that has been linked to the cancer phenotype. Due to the potential for recoding of protein coding sequences through A-to-I editing in mRNAs, aberrant editing can directly impact the proteome, leading to increased protein heterogeneity and the production of neoantigens. Patterns of overediting as well as underediting have been observed in cancer, affecting mRNAs as well as non-coding miRNA transcripts. For several other types of RNA modifications, including pseudouridine, 5-methylcytosine, 1-methyladenosine, and 7-methylguanosine, oncogenic or tumor suppressor functions have been ascribed to the molecular players involved. However, there is little understanding about the dynamic regulation and functional roles of these modifications in cancer biology.

Research Objectives

This NOSI is proposed to stimulate research on the role of RNA modifications in cancer biology by supporting small, investigator-initiated research grants. Gaining a better understanding of the roles of RNA modifications in cancer biology requires investigations into the what, where, when, how, and why of the processes that are inducing, regulating, and responding to these modifications. The studies proposed in response to this NOSI should be designed to generate key data for use as the foundation for future hypothesis-driven R01-type applications.

Research areas of interest for this NOSI include but are not limited to:

• Novel in vitro and in vivo methodologies and tools for the detection, mapping and quantification of chemical modifications of RNA molecules in cancer
• Improvements to existing methodologies to study RNA modifications, such as validation studies, increases in throughput, sensitivity, or utility
• Studies that establish mechanistic links between RNA modifications and the cancer phenotype using existing clinical resources
• Investigations on RNA modification-driven cancer formation in mammalian and non-mammalian Research Organisms
• Investigations on the dynamics of one or multiple types of RNA modifications driving cancer formation
• Characterization of writers, erasers, and readers of modifications and their cancer-associated de-regulation
• Advances in the understanding of crosstalk between two or more modes of RNA modification during cancer formation
• Identification of tumor cell vulnerabilities resulting from cancer-related changes in RNA modifications
• Identification of RNA modification signatures that can serve as potential biomarkers in cancer biology
• Mechanisms of how RNA modifications become de-regulated in cancer

Responsiveness

Applications that will be considered nonresponsive to this NOSI will include those focused on:

• Clinical trials

Application and Submission Information:

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) through the expiration date of this notice.

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

For funding consideration, applicants must include “NOT-CA-22-003” (without quotation marks) in the Agency Routing Identifier field (box 4b) of the SF424 R&R form. Applications without this information in box 4b will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Scientific/Research Contact(s)

Stefan Maas, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6230
Email: stefan.maas@nih.gov