# Project 2: Contribution of the Stromal Microenvironment to Early Dissemination

> **NIH NIH U54** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $352,446

## Abstract

PROJECT 2 – SUMMARY
Metastasis initiates early in melanoma, and coincides with phenotypic and functional changes in tumor cells,
surrounding stromal cells, and extracellular matrix components. Amongst the stromal cell types, cancer
associated fibroblasts (CAFs) are emerging as a particularly relevant cell population. Although they are
genetically stable, CAFs are phenotypically and functionally diverse and distinct subsets of CAFs were found to
support or inhibit cancerous growth in pancreatic cancer models. Although these findings suggest functionally
diverse sets of CAFs could also exist in other cancers, they have yet to be defined in most other cancer types.
Furthermore, because specific CAFs might be valuable prognostic markers or therapeutic targets, it is becoming
increasingly important to better understand their development and regulation. Here, we propose to investigate
how signals between melanoma cells and fibroblasts create heterogeneity within tumors and how this
heterogeneity unleashes metastatic behaviors in a subset of melanoma cells. To test this hypothesis, we
developed genetically engineered congenic mouse models that allow us to genetically manipulate melanocyte
stem cells to initiate tumors that faithfully recapitulate the pathology of human melanoma and to independently
inhibit specific genes in melanoma cells or CAFs. These models will uniquely enable us to investigate how
specific signaling mechanisms influence CAF functions in melanoma development and metastasis. We propose
to couple our mouse models with single-cell RNA sequencing, spatial transcriptomics, ATAC-seq, and ChIP-seq
approaches to transcriptionally define distinctive CAF states. We will also use them along with melanoma
specimens from patients with and without metastatic progression to map specific CAFs and their proximity to
other cell types with highly multiplexed immuno-histochemistry (Aim 1). Next, we will use these tools and data to
discover cell state specific receptor-ligand interactions and study how IGF1-IGF1R signaling between melanoma
cells and CAFs –one model pathway our preliminary studies identified – influences intratumor heterogeneity and
metastatic progression in vivo (Aim 2).
 Project 2 will leverage the pathological, technological, and analytical resources of Cores B and C. It will
synergize with Project 1 to determine whether and how melanoma cells interact with distinctive CAFs and how
these interactions allow for metastatic dissemination. Project 2 will also enhance Project 3 by shedding new light
onto CAF-secreted cytokines that modulate tumor draining lymph nodes and make immune cells tolerant to
metastasizing melanoma cells. Once we understand these processes on a molecular level and link them to
clinical characteristics, we can begin to inform patient selection for adjuvant therapy in early-stage melanoma
and catalyze a rational development of targeted therapies that prevent or treat metastatic dissemination in early-
stage melanoma ...

## Key facts

- **NIH application ID:** 10414445
- **Project number:** 1U54CA263001-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Mayumi Ito
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $352,446
- **Award type:** 1
- **Project period:** 2022-09-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10414445

## Citation

> US National Institutes of Health, RePORTER application 10414445, Project 2: Contribution of the Stromal Microenvironment to Early Dissemination (1U54CA263001-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10414445. Licensed CC0.

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