# Effect of the plantar skin microenvironment on tumor metastasis and drug tolerance

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $426,082

## Abstract

Project Summary
Patients with advanced acral melanoma (AM) suffer worse outcomes relative to patients with cutaneous
melanoma (CM), in part, because they do not respond as well to treatments approved for CM including immune
checkpoint blockade and BRAFV600E inhibitor strategies. Tailored therapies are warranted for patients with
advanced AM given that AMs differ from CMs in a) cell of origin (volar melanocytes versus non-volar
melanocytes, respectively) and b) mutational frequencies in targetable driver genes (e.g., BRAF hotspot
mutations in 18% of AMs versus 46% of CMs). In this application, we focus on the unique biological
dynamics induced by the plantar skin microenvironment of the foot where AMs most commonly arise
in. The plantar microenvironment is mechanically stiffer relative to non-plantar skin sites (e.g., arm) where CMs
arise, and the resident dermal fibroblasts in plantar skin display cancer associated fibroblast (CAF)-like markers
in the absence of cancer cells. In the first aim, we will mechanistically define how matrix stiffness impacts AM
metabolism. Our preliminary data identify elevated lysosome catabolism and collagen degradation gene
signatures in AM cells grown in the stiffer plantar skin of the foot versus softer non-plantar skin of the flank in
mice. We will track changes in lysosomal catabolism in a panel of in vitro and in vivo AM model systems using
a) live cell reporters (e.g., mCherry-eGFP-LC3), b) Western blotting of protein markers of lysosome activity
(e.g., LC3B, p62, NBR1), and c) bulk and single cell RNA sequencing analyses. In the second aim, we are
testing the hypothesis that matrix stiffness-induced lysosomal catabolism promotes metastasis to the liver and
insensitivity to CDK4/6 inhibitor therapy. These studies will not only determine whether liver metastasis and
therapy resistance emerge via elevated lysosomal catabolism, but will also provide us with information on the
relationship between matrix stiffness and lysosomal catabolism that will extend to other tumor types including
breast and pancreatic where tissue stiffening is associated with poorer survival. In the third aim, we are testing
the hypothesis that plantar fibroblasts promote AM metastasis and therapy resistance through the secretion of
factors including matrix gla protein (MGP). We expect that targeting separate aspects of the plantar skin
microenvironment in a rationally designed way (in vitro and then in preclinical in vivo models) will enable the
reduction of resistance onset and metastatic disease in patients.

## Key facts

- **NIH application ID:** 10857995
- **Project number:** 1R01CA289514-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Vito William Rebecca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $426,082
- **Award type:** 1
- **Project period:** 2024-09-11 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10857995

## Citation

> US National Institutes of Health, RePORTER application 10857995, Effect of the plantar skin microenvironment on tumor metastasis and drug tolerance (1R01CA289514-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10857995. Licensed CC0.

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