# Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $387,200

## 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.
Unlike proliferation and apoptosis, cell fate choices are currently assessed using qualitative or indirect assays.
As a result, we lack full understanding of how progenitors balance proliferation with differentiation during skin
development and homeostasis, or in growth disorders of the skin.
 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 developed a novel assay to directly quantify
rates of progenitor cell self-renewal and differentiation in epidermis during homeostatic and hyperproliferative
growth. We will employ our assay in the mouse models engineered to express physiological levels of
constitutively active Hras and Pik3ca in the skin. In addition, we will use our recently developed rapid gene-
targeting method, to explore how specific effectors and substrates of RAS-PI3K signaling modify epidermal
differentiation in vivo.
 This application aims to test the hypotheses that: 1.) Increased differentiation can balance mitogenic
effects of oncogenic signaling to maintain tissue homeostasis; 2.) Ras effector Pik3ca initiates a molecular
cascade that includes Akt and specific Akt substrates to regulate progenitor cell renewal and differentiation in
skin epidermis; and 3.) Epidermal progenitor response to oncogene expression is heterogeneous and
influenced by progenitor cell niche.
 The results of our research are expected to immediately uncover cellular and molecular principles that
maintain skin homeostasis and functionality despite the abundance of growth-promoting mutations. These
findings will be a critical step in development of pharmacological strategies to manipulate progenitor cell
potential in the epidermis, to treat conditions marked by unrestrained tissue growth.

## Key facts

- **NIH application ID:** 9970189
- **Project number:** 5R01AR070780-04
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Slobodan Beronja
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,200
- **Award type:** 5
- **Project period:** 2017-07-27 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970189

## Citation

> US National Institutes of Health, RePORTER application 9970189, Differentiation balances oncogene-driven proliferation to maintain epidermal homeostasis (5R01AR070780-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9970189. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*