# Role of Hypoxia in Shaping the Tumor Stroma in Pancreatic Cancer

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $407,542

## Abstract

ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest and most aggressive cancer types, and
thus new treatment strategies are urgently needed. Pancreatic cancer cells are surrounded by a dense stroma
consisting of extracellular matrix and noncancerous cells, including fibroblasts and immune cells. Interactions
between tumor cells and the associated stroma are critical for tumor progression and resistance to therapy. Due
to the unusually low vascular density of PDAC, both the tumor and stromal cells experience hypoxia, a condition
of insufficient oxygen availability. To cope with hypoxic stress, both the tumor and stromal compartments
undergo adaptive changes primarily mediated by hypoxia-inducible factor 1ɑ and 2ɑ (HIF1ɑ and HIF2ɑ).
Although PDAC is known to be severely hypoxic and hypoxia predicts poor clinical outcome, the effects of
hypoxia and stromal HIF activation on tumor-stroma interactions in PDAC are not fully understood. Based on
our preliminary observation that inflammatory fibroblasts and macrophages are preferentially located in hypoxic
tumor regions whereas CD8+ T cells are largely excluded from hypoxic regions in PDAC, we hypothesize that
hypoxia drives an immunosuppressive microenvironment by promoting an inflammatory fibroblast phenotype
and in turn modulating infiltration and function of macrophages and CD8+ T cells. In Specific Aim 1, we will
determine how hypoxia and HIFs regulate an inflammatory fibroblast phenotype in PDAC using a three-
dimensional (3D) coculture system of pancreatic tumor cells and fibroblasts and exposing the coculture to either
hypoxia or normoxia, as well as using mouse models lacking fibroblast expression of HIF1ɑ or HIF2ɑ. In Specific
Aim 2, we will define how hypoxia-induced fibroblast-secreted factors and macrophage-intrinsic hypoxic
responses regulate macrophage recruitment and function in PDAC by treating macrophages with conditioned
media derived from 3D tumor cell-fibroblast cocultures under hypoxia, and using mouse models lacking myeloid
expression of HIF1ɑ or HIF2ɑ. In Specific Aim 3, we will determine how macrophages and fibroblasts contribute
to CD8+ T cell exclusion in hypoxic tumor niches by depleting macrophages or blocking a factor secreted from
fibroblasts in syngeneic orthotopic transplanted tumors, injecting a hypoxia probe into mice, and assessing CD8+
T cell infiltration and activation in hypoxic and normoxic tumor regions. Together, the proposed studies will
provide new knowledge on hypoxic regulation of the tumor-stroma crosstalk and inform the optimal design of
stroma-targeting therapeutic strategies for PDAC.

## Key facts

- **NIH application ID:** 10823338
- **Project number:** 5R01CA269025-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Kyoung Eun Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $407,542
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823338

## Citation

> US National Institutes of Health, RePORTER application 10823338, Role of Hypoxia in Shaping the Tumor Stroma in Pancreatic Cancer (5R01CA269025-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10823338. Licensed CC0.

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