# Immune control of oncogene selection in preneoplastic colon

> **NIH NIH K08** · YALE UNIVERSITY · 2024 · $185,314

## Abstract

Colon cancers develop by stepwise accumulation of oncogenic mutations in epithelial stem
cells. These mutated stem cells multiply by positive selection in healthy colon for years before
transforming into cancers. In this proposal I aim to unravel an immune surveillance mechanism
that prevents selection of mutated stem cells in healthy colon. Colon cancers with BRAFV600E
mutation involve the proximal colon and disproportionately affect women above the age of 65
years. Based on the unique anatomic and demographic distribution of these cancers, I propose
that BRAFV600E mutated stem cells have a strong selective advantage in the proximal colon.
Regulatory T cells are part of the colonic stem cell microenvironment and, also heavily infiltrate
BRAFV600E mutated cancers. Thus, I hypothesize that the regulatory T cells recognize and
suppress the selection of BRAFV600E mutated stem cells in the healthy colon. To test this
hypothesis, I have developed several genetically inducible lineage tracing mice that specifically
induce BRAFV600E mutation in a single colonic stem cell. Using these mice, I will dissect the
molecular mechanisms employed by regulatory T cells to perform surveillance against
BRAFV600E mutated stem cells. Establishing the role of regulatory T cells in oncogene
selection will lead to development of immune-prevention therapies against colon cancers. The
proposal also includes a rigorous training program under the guidance of mentors with expertise
in tumor immunology, stem cell biology and cancer evolution. Completion of the proposed
activities will help me realize my goal of becoming an independent physician-scientist,
investigating immune preventive strategies against colon cancer.

## Key facts

- **NIH application ID:** 10929458
- **Project number:** 5K08CA277003-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Haris Mirza
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $185,314
- **Award type:** 5
- **Project period:** 2023-09-14 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929458

## Citation

> US National Institutes of Health, RePORTER application 10929458, Immune control of oncogene selection in preneoplastic colon (5K08CA277003-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10929458. Licensed CC0.

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