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Mechanisms and Regulation of Epigenetic Barriers to Stem Cell Transformation in Colorectal Cancer

Award Number: K99CA293236
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/04/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Mechanisms and Regulation of Epigenetic Barriers to Stem Cell Transformation in Colorectal Cancer - Project Summary Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Despite wellcharacterized genetic drivers (APC, KRAS, TP53, and SMAD4), recurrence remains high, and the 5-year survival rate for advanced CRC is only ~15%. A major challenge is the persistence of cellular plasticity that allows nonstem tumor cells to reacquire stemness following therapy, driving tumor regrowth and relapse. My research addresses a central unresolved question: how stem cell transformation is epigenetically regulated during CRC initiation and progression. My preliminary studies reveal that the repressive histone modification H3K27me3 establishes an epigenetic gatekeeping barrier that restricts stemness programs to bona fide intestinal stem cells. During APC-driven transformation, this barrier is eroded, unleashing stemness and fetal transcriptional programs, activating onco-enhancers, and promoting tumor initiation. Genetic or chemical modulation of this barrier alters tumor growth, indicating that sustaining this repressive landscape can suppress transformation. The central hypothesis is that the H3K27me3-based epigenetic barrier tightly regulates stemness, and its erosion drives stem cell transformation and CRC progression. Restoring or maintaining this barrier will limit oncogenic plasticity and suppress tumor initiation. In the K99 phase, I will (1) define how strengthening or weakening the H3K27me3 barrier affects stem cell transformation and tumor growth in vivo (Aim 1), and (2) determine how this barrier evolves across sequential APC, KRAS, and TP53 mutations in engineered human colonoids (Aim 2). In the R00 phase, I will investigate how distinct founding mutations (APC versus BRAF) rewire H3K27me3 and DNA methylation programs to shape tumor evolution using single-cell DNA methylation profiling (Aim 3). The majority of this project uses engineered human colonoids to investigate cell-intrinsic epigenetic mechanisms of CRC progression (Aims 2 and 3). Complementary genetic mouse models are needed only for Aim 1 because the proposed studies address biological questions that cannot be answered using human colonoids or in silico approaches. Human colonoids cannot recapitulate native crypt architecture, physiological signaling gradients, or the longitudinal process of adenoma formation within intact tissue. Therefore, complementary genetic mouse models are required to test whether manipulation of the H3K27me3 epigenetic barrier alters stem cell transformation and tumor initiation within the native intestinal environment and to provide the in vivo context needed to interpret the mechanistic and cell-intrinsic findings from Aims 2 and 3. Highly sensitive low-input genomic and epigenomic assays developed in my laboratory further reduce animal use by maximizing the molecular information obtained from each specimen, enabling comprehensive multi-omic analyses from limited tissue without compromising statistical rigor. Collectively, my integrated approach will elucidate how genetic and epigenetic mechanisms cooperate to control stem cell transformation, uncovering therapeutic strategies to block cellular plasticity and prevent CRC recurrence.


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 = $135,163 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cancer Research Manpower	000	1	8/4/2026	NEW	$135,163
														Subtotal = $135,163

Grand Total All Awards = $135,163

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Mechanisms and Regulation of Epigenetic Barriers to Stem Cell Transformation in Colorectal Cancer

Award Number: K99CA293236

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/04/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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