# Reprogramming of the stromal microenvironment in melanoma progression and therapeutic escape

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $357,712

## Abstract

Although the approval of novel targeted therapy drugs, such as BRAF inhibitors (BRAFi), MEK inhibitors (MEKi),
and immune checkpoint inhibitors, has revolutionized melanoma treatment, long-term outcomes are still
disappointing for many patients because of the development of drug resistance. A major contributing factor to
tumor resilience and relapse is the presence of a “plastic” microenvironment, which is comprised of
heterogeneous stromal cell populations embedded in a dense and stiff extracellular matrix (ECM). Particularly,
the ECM not only functions as a barrier to drug penetration and distribution and also provides structural and
adaptive signals, which can induce therapeutic escape pathways in melanoma cells. Genetically stable cancer-
associated fibroblasts (CAFs) are known to be a notorious ECM-remodeling machine in the tumor stroma. We
have discovered that the number of CAFs with nuclear β-catenin in the melanoma stroma increases significantly
after the patients are treated with BRAFi/MEKi. We have established that increased nuclear β-catenin in CAFs
is induced by BRAFi but not MEKi. Nevertheless, how BRAFi stimulates CAFs to reprogram their biological
functions via hyperactivated nuclear β-catenin activity remains to be understood. We have obtained compelling
data demonstrating that targeted depletion of β-catenin in CAFs ablates their ability to remodel the tumor
microenvironment, downregulates abnormal BRAF/MAPK/ERK signaling in melanoma cells, and suppresses
melanoma cell drug resistance in vitro and in vivo. RNA-Seq data show that β-catenin is essential for CAF to
remodel the ECM by coining the CAF transcriptome. We have identified the β-catenin/TCF4 target gene periostin
(POSTN) as an important matricellular protein secreted by CAFs to promote BRAFi resistance. The central
hypothesis is that decoding and targeting the ECM-remodeling CAFs has the potential to create a drug-sensitive
microenvironment that sensitizes melanoma cells to therapeutic agents and increase their response rate. In Aim
1, we will elucidate the pro-activation pathway(s) by which BRAFi stimulates CAFs to mediate melanoma drug
resistance phenotypes. We will assess the role of hyperactivated nuclear β-catenin in the function of CAFs in
melanoma. In Aim 2, we will determine whether the β-catenin-TCF4 transcriptional complex is the signaling hub
that controls CAF-driven ECM remodeling and BRAFi/MEKi resistance. We will evaluate whether disrupting the
β-catenin-TCF4 interaction in CAFs will sensitize BRAF-mutant melanoma cells to BRAFi/MEKi in vivo. In Aim
3, we will determine the roles of CAF-derived POSTN in melanoma cell growth and resistance to BRAFi/MEKi.
We will investigate signaling pathways that are activated by POSTN in melanoma cells to promote their
proliferation and resistance to BRAFi. The expected outcomes are to be an in-depth mechanistic characterization
of the complex interactions among CAFs, BRAFi, and the ECM microenvironment that promote the grow...

## Key facts

- **NIH application ID:** 10430243
- **Project number:** 5R01CA249737-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Yuhang Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $357,712
- **Award type:** 5
- **Project period:** 2021-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430243

## Citation

> US National Institutes of Health, RePORTER application 10430243, Reprogramming of the stromal microenvironment in melanoma progression and therapeutic escape (5R01CA249737-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10430243. Licensed CC0.

---

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