# Epigenetic Regulation of Cutaneous Tumorigenesis

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2022 · $235,763

## Abstract

Project Summary/Abstract:
This proposal describes a five-year career development program designed to support an academic, physician-
scientist career. The proposed research project will capitalize on the expertise and resources available at
Washington University School of Medicine, which has a strong tradition of developing physician-scientists. Dr.
Timothy Ley, an expert in cancer genomics and epigenetics, and a recipient of multiple mentorship awards
nationally and at Washington University, will serve as the primary research mentor. The ultimate goal of the
candidate is to be an independent investigator in an academic medical center, studying epigenetic control of
cutaneous carcinogenesis, and caring for patients with cutaneous malignancies.
The long-term goal of this study is to define alterations in the epigenetic “state” of epidermal
keratinocytes that arise during normal aging and their roles in creating age-related susceptibilities for
skin cancer. Increasing age and UV light exposure are the two most prominent epidemiologic risk factors for
the development of skin cancer in fair skinned populations. Recent studies have identified clonal expansions of
cells harboring oncogenic mutations from clinically normal skin, suggesting that additional genetic or epigenetic
events are required for transformation to skin cancer. Aging and UV light exposure not only cause DNA
damage and mutations, but also have been demonstrated to cause DNA methylation changes in the skin of
human patients; whether these alterations are relevant for skin cancer pathogenesis is currently unknown. Our
preliminary data suggests that the DNA methylation state of epidermal cells undergoes a programmed change
at specific loci in mice as they age, as do stereotypical changes in gene expression resulting in the
development of a population of cells that we have named “basal aging-signature keratinocytes” (BASKs). We
will explore the hypothesis that age-related epigenetic changes, including DNA methylation, may increase
susceptibility to skin cancer development with the following specific aims: Aim 1: We will define the epigenetic
events in murine epidermis that result from normal aging, relate them to functional changes, and assess their
roles in the development of skin cancers. We will define the epigenetic changes in BASK cells, define
biomarkers that allow for the purification of this population, and test the susceptibility of aged skin to KRASG12D-
mediated skin tumorigenesis and the development of UVB-induced, mutated Trp53 clonal islands in the skin.
Aim 2: We will define the roles of individual DNA methyltransferases for the development of age-dependent
methylation states and for the neoplastic transformation of skin. Using mice conditionally deficient in Dnmt1,
Dnmt3a, and/or Dnmt3b in epidermal cells, we will determine whether these enzymes contribute to age-related
development of the BASK phenotype, and whether their deficiencies are relevant for KRASG12D-mediated sk...

## Key facts

- **NIH application ID:** 10455113
- **Project number:** 5K08CA237727-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David Chen
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $235,763
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455113

## Citation

> US National Institutes of Health, RePORTER application 10455113, Epigenetic Regulation of Cutaneous Tumorigenesis (5K08CA237727-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10455113. Licensed CC0.

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