Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer

Ashley M Mello; Tenzin Ngodup; Yusoo Lee; Katelyn L Donahue; Jinju Li; Arvind Rao; Eileen S Carpenter; Howard C Crawford; Marina Pasca di Magliano; Kyoung Eun Lee

doi:10.1038/s41389-022-00434-2

Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer

Oncogenesis. 2022 Sep 15;11(1):56. doi: 10.1038/s41389-022-00434-2.

Authors

Ashley M Mello^#¹, Tenzin Ngodup^#², Yusoo Lee², Katelyn L Donahue³, Jinju Li⁴, Arvind Rao^{4

5

6

7}, Eileen S Carpenter⁸, Howard C Crawford^{4

9

10}, Marina Pasca di Magliano^{4

11

12}, Kyoung Eun Lee^{13

14}

Affiliations

¹ Program in Immunology, University of Michigan, Ann Arbor, MI, 48109, USA.
² Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA.
³ Program in Cancer Biology, University of Michigan, Ann Arbor, MI, 48109, USA.
⁴ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
⁵ Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
⁶ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
⁷ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
⁸ Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, 48109, USA.
⁹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁰ Henry Ford Pancreatic Cancer Center, Henry Ford Health System, Detroit, MI, 48202, USA.
¹¹ Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA.
¹² Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.
¹³ Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA. kyoungle@umich.edu.
¹⁴ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA. kyoungle@umich.edu.

^# Contributed equally.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive fibroinflammatory stroma and often experiences conditions of insufficient oxygen availability or hypoxia. Cancer-associated fibroblasts (CAF) are a predominant and heterogeneous population of stromal cells within the pancreatic tumor microenvironment. Here, we uncover a previously unrecognized role for hypoxia in driving an inflammatory phenotype in PDAC CAFs. We identify hypoxia as a strong inducer of tumor IL1ɑ expression, which is required for inflammatory CAF (iCAF) formation. Notably, iCAFs preferentially reside in hypoxic regions of PDAC. Our data implicate hypoxia as a critical regulator of CAF heterogeneity in PDAC.

Abstract

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