# Origins and functions of pancreatic cancer-associated fibroblasts

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $355,498

## Abstract

PROJECT SUMMARY/ABSTRACT
The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. In solid tumors
featuring a prominent stromal reaction, an improved understanding of the functions and origins of abundant
stromal cell types may facilitate the development of new and effective therapies. Pancreatic ductal
adenocarcinoma (PDAC) is the quintessence of a fibro-inflammatory malignancy, with 50-90% of tumor volume
occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type which
drives the stromal reaction in PDAC, and recent reports suggest that stromal CAFs represent a heterogeneous
population of cells from diverse origins, potentially including cell types which support and others which
suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas which can
transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of
fibroblasts in the PDAC tumor microenvironment. However, proper lineage tracing studies have never been
performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are
unknown. Here we will take advantage of a novel mouse model we have developed to track PSC
differentiation and function during pancreatic tumor progression in vivo. We hypothesize that PSC-derived
fibroblasts in the PDAC microenvironment are a pro-inflammatory and tumor-supportive subset of PDAC CAFs,
and thus represent a viable therapeutic target. Our preliminary data support the notion that PSCs contribute to
only a subset of the CAF population in the tumor microenvironment, and the functions of these distinct
populations are entirely unknown. Our data to date also highlight a potential role for genetic alterations in the
epithelial compartment in orchestration of stromal fibroblast evolution. PDAC stromal heterogeneity and
functional significance will be interrogated with the following specific aims. Aim 1: Determine the role of PSC-
derived CAFs in pancreatic tumorigenesis. A novel mouse model will be used to ablate PSC-derived CAFs
for the first time and analyze the impact on tumor growth, survival, and organization of the tumor
microenvironment. Aim 2: Assess the consequence of tumor genotype in pancreatic cancer stromal
evolution. Motivated by preliminary data, we will use our reporter mouse model and patient samples to
analyze the interaction between p53 status in tumor cells and stromal CAF evolutionary routes, with important
potential implications for tumor phenotype and therapy responses. Aim 3: Define the role of PSC-derived
CAFs in therapy response and resistance. As PSC-derived CAFs express a transcriptional program
associated with resistance to chemotherapy and immunotherapy, we will determine the effect of these CAFs
on treatment response in vivo. These findings will shed light on mechanisms and consequences of stromal
evolution during pancreatic tumorigenesis...

## Key facts

- **NIH application ID:** 10201935
- **Project number:** 1R01CA250917-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Mara H. Sherman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $355,498
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201935

## Citation

> US National Institutes of Health, RePORTER application 10201935, Origins and functions of pancreatic cancer-associated fibroblasts (1R01CA250917-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10201935. Licensed CC0.

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