# Hypoxic regulation of macrophage migration and function via fibroblast reprogramming in pancreatic cancer

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $42,094

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United
States despite representing only 2% of all cancer cases. PDAC is characterized by an extensive
fibroinflammatory stroma and a hypoxic microenvironment, which contributes to disease progression and
therapeutic resistance. Macrophages and cancer-associated fibroblasts (CAFs) are the predominant cell types
within the PDAC stroma. Macrophages are a major immunosuppressive population in PDAC. These cells are
highly plastic and, as a result, their environment plays an important role in regulating their function. Macrophages
adapt to hypoxia, a condition of low oxygen availability, primarily through the stabilization of oxygen-liable
transcription factors called hypoxia-inducible factors (HIFs). Although PDAC is extremely hypoxic and both the
tumor cells and stromal cells experience hypoxia, the effects of hypoxia and HIFs on macrophages and their
communication with other stromal cells in PDAC remain largely unknown. Our group has recently found that
hypoxia promotes the acquisition of inflammatory cancer-associated fibroblasts (inflammatory CAFs), a recently
defined PDAC fibroblast subtype that produces high levels of inflammatory cytokines and chemokines. By
injecting a hypoxia probe into mice bearing PDAC, we have observed that inflammatory CAFs and macrophages
predominantly reside in hypoxic tumor regions compared with normoxic regions whereas T cells are largely
excluded from hypoxic tumor areas. Based on these preliminary data, I hypothesize that inflammatory fibroblasts
induced by hypoxia promote macrophage infiltration into hypoxic tumor regions and facilitate an
immunosuppressive macrophage phenotype. This hypothesis will be investigated with the following two Aims:
(1) to determine the role of hypoxia-induced fibroblast-secreted factors in regulating macrophage migration and
function in PDAC and (2) to define the role of macrophage HIFs in regulating macrophage migration and function
in PDAC. To complete Aim 1, I will culture macrophages with conditioned media derived from mono- and co-
cultures of pancreatic tumor cells and fibroblasts under either hypoxia or normoxia, and then assess the
expression of immunosuppressive macrophage markers as well as their migration. To complete Aim 2, I will
culture HIF1α-deficient and HIF2α-deficient macrophages under hypoxia with fresh media or conditioned media
from co-cultures of pancreatic tumor cells and fibroblasts under hypoxia. Then I will assess the expression of
immunosuppressive markers in these macrophages and evaluate their migration. Finally, I will define the role of
macrophage HIFs in mediating pancreatic tumorigenesis using orthotopic tumors from mice lacking myeloid
expression of HIF1ɑ or HIF2ɑ. My proposal will provide new insights into how hypoxia promotes an
immunosuppressive PDAC microenvironment by modulating the macrophage-fibroblast crosstalk, and ultimately
infor...

## Key facts

- **NIH application ID:** 10929976
- **Project number:** 5F31CA281194-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Sean Matthew Hannifin
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,094
- **Award type:** 5
- **Project period:** 2023-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929976

## Citation

> US National Institutes of Health, RePORTER application 10929976, Hypoxic regulation of macrophage migration and function via fibroblast reprogramming in pancreatic cancer (5F31CA281194-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10929976. Licensed CC0.

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