# Project 3: Role of the pancreatic fibroinflammatory microenvironment in obesity-promoted pancreatic cancer

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $255,118

## Abstract

PROJECT SUMMARY
Obesity increases the risk of developing pancreatic adenocarcinoma (PDAC), but the mechanisms underlying
these effects and the precise role played by the tumor stroma are not well understood. Using mice with pancreas-
specific expression of oncogenic mutant Kras (KC mice), obesogenic diets were found to markedly increase the
number of activated stromal myofibroblasts (aka pancreatic stellate cells, PaSC) and their deposition of
extracellular matrix (ECM) proteins, especially those promoting matrix stiffening. Obesity-induced changes in the
pancreatic fibrotic stroma are associated with increased numbers of macrophages and levels of various
cytokines, chemokines and growth factors with immunomodulation capacity, acceleration of the progression of
the tumor and increased incidence of invasive PDAC. Although the data strongly suggest a pro-tumor role for
stromal PaSC in obesity-induced PDAC promotion, the precise role(s) of these cells in PDAC and their
phenotypic characteristics appear more complex than initially perceived. Studies provided evidence that the
extracellular signals insulin, insulin-like growth factor 1 (IGF-1), leptin, LPS and selected interleukins; and
intracellular signals including mTOR/Akt, STAT3, and yes-associated protein 1 (YAP) play key roles in regulating
PaSC phenotypes and in promoting the pro-cancer effects of PaSC. These effects are likely mediated by PaSC
fibroinflammatory signals that boost tumor cell growth and induce apoptosis resistance. Moreover, PaSC were
found to regulate tumor macrophage differentiation into immunosuppressive phenotypes conducive of tumor
progression. Of interest are recent findings from retrospective analysis of large databases that patients with
PDAC have significantly improved outcome and longer disease-free survival if they take simvastatin. Also, pilot
studies indicate that metformin can modulate PaSC responses by regulating cellular metabolism, autophagy and
expression of fibro-inflammatory mediators. In this proposal, the hypothesis is that obesity produces unique
signals in the microenvironment of developing PDAC that are responsible for phenotypic alterations in
the PaSC so that they produce factors that promote proliferation and apoptosis resistance in the cancer
cells as well as shift the immune response to a pro-tumor state. It is also anticipated that simvastatin
and metformin attenuate this PaSC promotion and may be useful for prevention of obesity-induced
PDAC development. This hypothesis will be tested by (1) determining the consequences of selective elimination
of PaSC in KC mice on obesity-induced PDAC promotion; (2) establishing the pathways and cellular processes
in the stromal PaSC responsible for the pro-cancer phenotype promoted by obesity; (3) elucidating crosstalk
between PaSC, cancer cells and tumor macrophages; and (4) determining the effects of simvastatin in
combination with metformin on the pro-tumor phenotype of PaSC observed in the obese mice. In s...

## Key facts

- **NIH application ID:** 9928713
- **Project number:** 1P01CA236585-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Stephen J. Pandol
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $255,118
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928713

## Citation

> US National Institutes of Health, RePORTER application 9928713, Project 3: Role of the pancreatic fibroinflammatory microenvironment in obesity-promoted pancreatic cancer (1P01CA236585-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9928713. Licensed CC0.

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