# Co-Evolution Mechanisms of Pre-Cancer-Immune Interactions in Shaping Adaptive Cytotoxicity and Myeloid-Derived Suppression

> **NIH NIH U54** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $395,387

## Abstract

PROJECT SUMMARY/ABSTRACT
Project 3: Co-Evolution Mechanisms of Pre-Cancer-Immune Interactions in Shaping Adaptive
Cytotoxicity and Myeloid-Derived Suppression
The pre-cancer-to-cancer transition is a critical juncture in colorectal cancer (CRC) biology that has clinical value
in prevention and surveillance. This transition is characterized by an “evolutionary arms race” where the body’s
immune system seeks to eliminate the tumor while the tumor cells evolve mechanisms to suppress and evade
the immune system. The small number of human pre-precancers that transition into cancer precludes effective
predictive modeling of critical genetic and microenvironmental factors that drive these alterations. Herein, we will
leverage regional intratumoral heterogeneity, due to asynchronicity of evolution, with spatially resolved profiling
technologies on human tumor specimens to build trajectories of pre-cancer transition into malignancy. We will
model two pathways of pre-cancer transitions, the conventional pathway driven by mutations in the WNT
pathway and the serrated pathway characterized by an immunogenic microenvironment. Our previous pre-
cancer atlas describes a dichotomy between stemness in tumor cells and cytotoxic T cells in the
microenvironment between these two pathways. Thus, we hypothesize that pre-cancers gain stemness to enable
epithelial mechanisms to suppress a cytotoxic immune environment, resulting in malignant evolution. In Aim 1,
we will use spatially resolved DNA sequencing to map genetic evolution of pre-cancer cells with selective
pressures conferred by neoantigen-specific adaptive immunity. In Aim 2, we will use integrative spatial multi-
omics to interrogate tumor mechanisms to modulate immune cell communication networks during progression.
By combining novel technologies with data-driven systems modeling, we will shed light on the complex interplay
between human tumors and their microenvironment that shape their transition trajectories into malignancy.

## Key facts

- **NIH application ID:** 10926865
- **Project number:** 5U54CA274367-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Ken S Lau
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,387
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10926865

## Citation

> US National Institutes of Health, RePORTER application 10926865, Co-Evolution Mechanisms of Pre-Cancer-Immune Interactions in Shaping Adaptive Cytotoxicity and Myeloid-Derived Suppression (5U54CA274367-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10926865. Licensed CC0.

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