# CANCER ASSOCIATED FIBROBLAST CLONALITY, CHROMATIN ACCESSIBILITY AND THERAPEUTIC TARGETING IN PANCREATIC DUCTAL ADENOCARCINOMA STROMA

> **NIH NIH F32** · STANFORD UNIVERSITY · 2020 · $53,403

## Abstract

PROJECT SUMMARY
Solid tumors such as pancreatic ductal adenocarcinoma (PDAC) are comprised of transformed cancer cells
along with a participatory population of stromal cells. These include cancer-associated fibroblasts
(CAFs), which
are known to provide fibrotic stroma (desmoplasia), which supports tumor proliferation. My preliminary data
suggest that fibroblasts in solid tumor stroma are locally-recruited and activated, and proliferate in a highly clonal
manner. Such clonality suggests the presence of tissue-resident fibroblast progenitors. Changes in chromatin
accessibility are suspected to play a critical role in driving fibroblast activation. Characterization of activated
fibroblasts is a key step toward developing novel stromal therapies against cancer. In this project, I aim to 1)
quantitate the local, clonal expansion of activated fibroblasts in PDAC using the Rainbow mouse, a stochastic,
multi-colored, lineage-tracing model. I will use the EMBLEM (Epigenome and Mitochondrial Barcode of Lineage
from Endogenous Mutations) protocol, which analyzes somatic mutations in mitochondrial DNA from single cell
(sc)-assay for transposase-accessible chromatin (ATAC)-seq data to track cell lineages, in order to identify and
characterize putative fibroblast progenitors. To further explore the biology underlying fibroblast activation in
PDAC, I will 2) conduct sc-RNA-seq on mouse and human PDAC CAFs to identify functionally relevant changes
in gene expression that occur with fibroblast activation. I will correlate CAF gene expression patterns with
changes in chromatin accessibility based on the nuclear reads obtained in my sc-ATAC-seq dataset. DNA-
binding elements such as Ets1 which are known to trigger Focal adhesion kinase (FAK)-mediated signaling, and
FAK pathway signaling is suggested to play a significant role in CAF-associated desmoplasia in solid tumors.
My preliminary data suggest that PDAC CAFs show significant upregulation of CXCL5 and CXCL10 expression,
which are downstream chemokine targets of the FAK pathway. As such, I will 3) determine functional effects and
explore the therapeutic potential of modulating these chemokines in activated PDAC CAFs using in vitro and in
vivo assays. I will correlate modulation of these putative therapeutic targets with specific changes in chromatin
accessibility using protein-indexed (Pi)-ATAC, which permits correlation of chromatin accessibility with protein
expression at a single cell level.
The results of these aims will expand our understanding of CAF biology and
heterogeneity in PDAC. This project is expected to identify novel stromal targets that could be exploited
therapeutically either primarily or adjunctively in the setting of solid tumors.

## Key facts

- **NIH application ID:** 9909821
- **Project number:** 1F32CA239312-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Deshka Stonorov Foster
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $53,403
- **Award type:** 1
- **Project period:** 2020-01-15 → 2020-10-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9909821

## Citation

> US National Institutes of Health, RePORTER application 9909821, CANCER ASSOCIATED FIBROBLAST CLONALITY, CHROMATIN ACCESSIBILITY AND THERAPEUTIC TARGETING IN PANCREATIC DUCTAL ADENOCARCINOMA STROMA (1F32CA239312-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9909821. Licensed CC0.

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