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Investigating the function of aberrant RNA in cancer

Award Number: R37CA303323
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/04/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Investigating the function of aberrant RNA in cancer - Metastatic melanoma is the most lethal form of skin cancer. Emerging evidence implicates defective nuclear RNA surveillance in cancer, with accumulation of aberrant prematurely terminated RNAs (ptRNAs) directly promoting oncogenic phenotypes. Components of the CDK13 complex, which normally activate ptRNA degradation, are mutated in ~20% of melanomas, highlighting the clinical relevance of this pathway. The long-term objective is to define mechanisms of ptRNA-driven oncogenesis to enable targeted interventions. Because ptRNA stabilization does not alter full-length mRNAs or proteins, and nontranslatable ptRNAs still drive melanoma, ptRNAs likely act through a noncoding, gene-independent mechanism. Intronic sequence is a shared ptRNA feature, and removal of introns abolishes oncogenic activity. Our central hypothesis is that ptRNAs promote oncogenesis through a noncoding RNA mechanism that requires intronic sequences. Our preliminary studies indicate that aberrant RNA-mediated oncogenesis depends on whole-organism physiology that cannot be modeled in vitro. Zebrafish are the most appropriate animal model because RNA degradation mechanisms are conserved between zebrafish and humans and fish enable more rapid genetics than in vitro studies. Specific Aim 1 will define how ptRNAs contribute to oncogenesis. We will: (a) map minimal functional ptRNA sequences required for tumor acceleration using a zebrafish melanoma model, followed by validation in human melanoma cells; (b) identify proteins and (c) RNAs that bind minimal oncogenic sequences using RNA-centric approaches, including ChIRP-MS and O-MAP, in human melanoma cells; (d) determine ptRNA subcellular localization in CDK13-mutant human melanoma cells and zebrafish melanoma; and (e) test the roles of previously identified ptRNA-binding proteins and newly identified ptRNA-binding RNAs in regulating ptRNA stability and localization. Preliminary data show that ptRNAs are m6A-modified and bind m6A readers; VIRMA, an m6A writer, is recruited in a CDK13-dependent manner and is recurrently mutated in cancer. Specific Aim 2 will define how m6A regulates ptRNA stability and oncogenic activity. We will: (a) use direct RNA long-read sequencing to map ptRNA m6A deposition in CDK13-mutant and control human melanoma cells and zebrafish melanoma; (b) define how m6A deposition affects ptRNA stability in human melanoma cells and tumor-promoting activity in zebrafish; (c) measure the effects of recurrent VIRMA truncating mutations on ptRNA m6A deposition and stability in both systems; and (d) determine how VIRMA truncations alter the m6A deposition complex by immunoprecipitation-mass spectrometry in human cells. This work will define noncoding RNA mechanisms by which ptRNAs directly contribute to oncogenesis, including m6A-dependent pathways. Findings will inform oligonucleotide- and small-molecule-based therapies by identifying upstream regulators and downstream effectors. Because other cancers also harbor CDK13-complex mutations, these studies may benefit a broader patient population and provide a framework for investigating malignancies characterized by accumulation of intron-containing RNAs.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $569,552 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	1	9/4/2026	NEW	$569,552
														Subtotal = $569,552

Grand Total All Awards = $569,552

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Investigating the function of aberrant RNA in cancer

Award Number: R37CA303323

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/04/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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