# Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $588,572

## Abstract

Project Summary
 In skin epithelium, a population of progenitor cells distinctly capable of proliferation, self-renewal, and terminal
differentiation into post-mitotic progeny, is responsible to sustain tissue homeostasis throughout life. In particular,
the dynamic choice between renewal and differentiation has emerged as a critical regulator of the long-term fate
of epidermal progenitors with cancer-driver oncogenic mutations, which are either rapidly eliminated through
increased differentiation or tolerated as growth suppressed clones due to a stringent renewal/differentiation
equilibrium.
 Our long-term objective is to establish how epidermal progenitor cells balance growth in the presence of
oncogenic mutations to maintain tissue homeostasis. To do so, we will employ: (i) a mouse model that can initiate
expression of oncogenic Hras in a single epidermal progenitor, (ii) intravital imaging to document growth from a
single oncogenic cell to a stably integrated clone, (iii) a novel progenitor renewal assay to quantify dynamic cell
fate choices accompanying clone expansion, and (iv) our recently developed methods to modify gene function
in epidermal and stromal cells surrounding the oncogenic clone, to explore specific cellular and molecular
mechanisms we hypothesize function are the interface of oncogenic cells and their microenvironment, and
ensure skin homeostasis.
 This application aims to test the hypotheses that: 1.) Balanced progenitor renewal, critical to epidermal
tolerance of oncogenic mutations, is coordinated across the tissue through short- and long-range non-cell
autonomous interactions; 2.) Signaling between oncogenic clones and the surrounding normal epidermis,
mediated by traditional axon guidance molecules, is required for balanced progenitor renewal and skin
homeostasis; and 3.) Skin site-specific interaction between epidermal and stromal compartments can override
oncogenic tolerance and lead to loss of tissue homeostasis.
 The results of our research are expected to immediately integrate our growing understanding of cell
autonomous mechanisms of oncogenic tolerance into the broader, tissue-wide context critical to skin
homeostasis. We expect these findings to inform future development of comprehensive strategies, focused on
both the progenitor cell and its microenvironment, to manipulate its renewal potential and treat conditions marked
by unrestrained epidermal growth.

## Key facts

- **NIH application ID:** 10908719
- **Project number:** 5R01AR070780-08
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Slobodan Beronja
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $588,572
- **Award type:** 5
- **Project period:** 2017-07-27 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908719

## Citation

> US National Institutes of Health, RePORTER application 10908719, Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis (5R01AR070780-08). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10908719. Licensed CC0.

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