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Dissecting the non-mutational mechanisms of benign-to-malignant transition in colon cancer

Award Number: R01CA307963
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/16/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Dissecting the non-mutational mechanisms of benign-to-malignant transition in colon cancer - The purpose of this proposal Is to elucidate the rate-limiting non-mutational events underlying benign to malignant transition of colorectal cancer (CRC). Colon polyps are extremely common, occurring in up to 40% of adults Over 50, and are the precursors to CRC. While the causative mutations and their stepwise acquisition In this polyp-to-c:arcinoma sequence are well understood, the non-mutational mechanisms are not. In this proposal, we will use a new mouse model that emulates, for the first lime, the stepwise acquisition of mutations In the distal colon to accurately model benign-to-malignant transition In human CRC. Benign polyps are initialed via knockout of the moat commonly mutated gene in human colon polyps (Apc). The most common mutational events In advanced CRC (Kras G120, Trp53 loss) are then Induced In rare cells of established polyps wl1h spatial and temporal precision. In our preliminary studies, we have found 1hat this model accurately emulates the histopathological progression of benign-to-malignant transition of human CRC, but not in mice that are lacking T c:ells-these tumors do not progress beyond adenoma. Spatial transcriptomic (S1) analyses Of these tumors revealed that KrasG120 induces loss of signatures Of homeostatic regeneration and gain of a fetal intestinal- like stem cell state, which Is known to play a critical role In intestinal repair following injury and inflammation, KrasG120 regions within polyps were also less proliferative and depleted over time, consistent wi1h the slow cycling nature of injury-responsive stem cells in the c:olon. These findings establish that mutations, while necessary, are not sufficient to drive progression to CRC, at least when acquired In the stepwise sequence characteristic of human CRC. We hypothesize that malignant precursors in benign polyps despite having the necessary genetic mutations, require inflammatory signals to progress to cancer. These signals enable this transition by shifting the fitness landscape of the premalignant niche in favor of a fetal intestinal wound healing response over homeostatic regeneration. In Aim 1, we will leverage our innovative model to functionally interrogate the role of the fetal Intestinal state In benign-to-malignant transition by Inducing 1h18 slate via 1) wounding or non-specific T cell activation, 2) knocking out Its key transcriptional coordinator ( Yap), and 3) ablating cells in this Slate. we will use ST data from the model to define the transcriptional regulatory networks underlying this state In progressing versus non-progressing lesions. In Aim 2, we will identify rate-limiting microenvironmental factors that preferentially select for malignant precursor cells, and define the tranSC11pllonal mechanism by which these factors cooperates with, oncogenic mutations. Results will be validated against ST data we have generated on human polyps with early malignancy. Impact: completion Of !hie proposal will provide a mechanistic foundation for understanding why some benign polyps progress to cancer while most do not. This knowledge may nominate new and mare specific biomarkers for early cancer detection, as well as rate-limiting events that could be targeted fur cancer prevention.


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 = $704,182 )
2026	2026	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	1	6/16/2026	NEW	$704,182
														Subtotal = $704,182

Grand Total All Awards = $704,182

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Dissecting the non-mutational mechanisms of benign-to-malignant transition in colon cancer

Award Number: R01CA307963

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/16/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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