# Elucidating fibroblast/immune crosstalk and plasticity in pancreatic ductal adenocarcinoma

> **NIH NIH F31** · STATE UNIVERSITY NEW YORK STONY BROOK · 2022 · $2,500

## Abstract

Project Summary
Pancreatic ductal adenocarcinoma (PDA) is a deadly malignancy, and only 8% of patients diagnosed with this
cancer survive 5 years after diagnosis. The poor outcomes of patients with PDA are attributed to the advanced
stage of disease at the time of diagnosis and the lack of effective therapies, highlighting the need for new
approaches. PDA is characterized by an abundance of extracellular matrix (ECM) around the cancer cells,
referred to as a desmoplastic reaction. The desmoplasia provides a niche for different types of stromal cells,
including immune cells and cancer-associated fibroblasts (CAFs), which are derived primarily from pancreatic
stellate cells (PSCs). PDA CAFs have recently been found to display heterogeneity with distinct phenotypes and
spatial distributions: myofibroblastic CAFs (myCAFs) express high levels of α-smooth muscle actin (αSMA) and
are in direct physical contact with cancer cells, while inflammatory CAFs (iCAFs) are farther away from tumor
cells and secrete inflammatory cytokines. Although this finding has provided opportunities for new therapeutic
approaches, their interaction with other cell types within the immunosuppressive, tumor-promoting
microenvironment of PDA requires further study. Tumor-associated macrophages (TAMs) are prominent in PDA
tumors and are known to have an immunosuppressive function, making them an attractive therapeutic target.
However, the mechanisms through which TAMs signal to and impact the biology of iCAFs and myCAFs remains
to be explored. This study aims to understand the crosstalk between macrophages and the two CAF subtypes
and how these cell populations fluctuate during PDA progression. My preliminary studies show that PSCs
promote the proliferation and alternative activation of macrophages in vitro. In addition, in a genetically
engineered mouse model (GEMM) of pancreatic cancer, PanIN lesions (precursors of PDA) display an
abundance of both αSMA+ fibroblasts and alternatively activated macrophages in close proximity to each other.
These results suggest that the fibroblasts and macrophages signal to each other, contributing to the CAF and
macrophage phenotypes in PDA. To identify factors responsible for such crosstalk, I will use an innovative, three-
dimensional triple co-culture system that combines pancreatic ductal organoids, PSCs, and macrophages. To
better understand how the CAF subtypes impact tumor progression and macrophage phenotype in vivo, I will
engineer iCAF- and myCAF-conditional knockout mice and perturb each subtype in an orthotopically
transplanted organoid mouse model. Ultimately, the identification of iCAF/myCAF and macrophage dynamics
and interactions will illuminate the role these cells play in the disease, opening avenues for new and much-
needed therapeutic targets.

## Key facts

- **NIH application ID:** 10531296
- **Project number:** 3F31CA247416-02S1
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Jennifer Susan Thalappillil
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,500
- **Award type:** 3
- **Project period:** 2021-12-06 → 2023-02-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10531296

## Citation

> US National Institutes of Health, RePORTER application 10531296, Elucidating fibroblast/immune crosstalk and plasticity in pancreatic ductal adenocarcinoma (3F31CA247416-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10531296. Licensed CC0.

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