# An integrated approach to melanoma metastasis and therapy resistance: effects of age-related changes in the ECM and the biomechanics of the skin

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $105,092

## Abstract

Project Summary
Chronic inflammatory conditions such as aging and obesity harmonize with cancer cell mutations to trigger and
promote tumor development and progression. Hence, just like in melanoma, age plays an important role in
pancreatic cancer (PC). A unique aspect of solid cancers (including melanoma, colon, lung, PC and others) is a
non-cancer cell local reaction known as desmoplasia that, akin to chronic fibrosis, limits the normal organ function
and promotes a pro-tumor systemic inflammation. Of note, PC’s desmoplasia can encompass over 70% of the
tumor mass. Cancer-associated fibroblasts (CAFs) and their self-generated fibrous collagen rich extracellular
matrix (ECM) are the main desmoplastic components and together regulate numerous aspects of cancer
progression including drug resistance, immune cell regulation and metastasis. Importantly, while local fibroblasts
and their ECM maintain homeostatic equilibrium of a healthy organ and can even prevent tumor development,
chronically altered fibroblastic cells, like CAFs and their remodeled ECMs, sustain a dynamic reciprocity that
upholds the cancerous (i.e., chronically diseased) organ. Yet, clinical attempts to eliminate pancreatic CAF/ECM
render no benefit or were harmful to patients. Hence, “normalizing” the tumor microenvironment to harness its
anti-tumor effects, as opposed to eliminating desmoplasia, is sought by the tumor microenvironment field. We
and others have developed means to assess desmoplastic signatures using pathological samples. Of note, the
only clinical intervention with a curative intent in PC is surgery, and pre-operatively treating surgical patients with
chemo-radiation has been shown to often improve outcomes. A particular predicament of pre-operative chemo-
radiation is that if surgery did not successfully eliminate all cancerous cells, the treatment could “aggravate”
desmoplasia and promote fast progression of residual disease. One of the main known indicators of pro-tumoral
desmoplasia is TGFβ, and we have demonstrated that desmoplastic signatures representative of avid TGFβ
signaling are indeed predictive of short PC surgical patient overall survival. Published data using pre-clinical
models indicated that TGFβ, is systemically increased by classic chemo-radiation. Nonetheless, data showed
that if radiation is delivered in pulses, TGFβ levels are limited. This study proposes to conduct two specific aims:
 Aim1 will test if delivering radiation in pulses could “normalize” TGFβ secretion by human PC CAFs. For this
we will use our well-established laboratory culturing model of desmoplasia using patient CAFs and their ECM.
 Aim2 will test whether detecting and measuring PD CAFs indicative of limited TGFβ signaling could be used
as a desmoplastic indicator of improved patient outcomes. For this, we will use available pathological samples
to compare melanoma vs. PC desmoplastic features and query their clinical relevancies.
 The proposal was designed to augment our kn...

## Key facts

- **NIH application ID:** 10380313
- **Project number:** 3R01CA232256-03S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Edna Cukierman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $105,092
- **Award type:** 3
- **Project period:** 2021-07-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380313

## Citation

> US National Institutes of Health, RePORTER application 10380313, An integrated approach to melanoma metastasis and therapy resistance: effects of age-related changes in the ECM and the biomechanics of the skin (3R01CA232256-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10380313. Licensed CC0.

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