Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines Journal Article


Authors: Schwörer, S.; Cimino, F. V.; Ros, M.; Tsanov, K. M.; Ng, C.; Lowe, S. W.; Carmona-Fontaine, C.; Thompson, C. B.
Article Title: Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines
Abstract: Cancer-associated fibroblasts (CAF) are a major cell type in the stroma of solid tumors and can exert both tumor-promoting and tumor-restraining functions. CAF heterogeneity is frequently observed in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by a dense and hypoxic stroma that features myofibroblastic CAFs (myCAF) and inflammatory CAFs (iCAF) that are thought to have opposing roles in tumor progression. While CAF heterogeneity can be driven in part by tumor cell-produced cytokines, other determinants shaping CAF identity and function are largely unknown. In vivo, we found that iCAFs displayed a hypoxic gene expression and biochemical profile and were enriched in hypoxic regions of PDAC tumors, while myCAFs were excluded from these regions. Hypoxia led fibroblasts to acquire an inflammatory gene expression signature and synergized with cancer cell-derived cytokines to promote an iCAF phenotype in a HIF1α-dependent fashion. Furthermore, HIF1α stabilization was sufficient to induce an iCAF phenotype in stromal cells introduced into PDAC organoid cocultures and to promote PDAC tumor growth. These findings indicate hypoxia-induced HIF1α as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC. SIGNIFICANCE: Hypoxia in the tumor microenvironment of pancreatic cancer potentiates the cytokine-induced inflammatory CAF phenotype and promotes tumor growth. See related commentary by Fuentes and Taniguchi, p. 1560. ©2023 American Association for Cancer Research.
Keywords: pancreatic neoplasms; phenotype; metabolism; carcinoma, pancreatic ductal; pathology; pancreas carcinoma; cytokine; cytokines; pancreas tumor; fibroblast; fibroblasts; tumor microenvironment; cancer associated fibroblast; pancreatic ductal carcinoma; pancreatic carcinoma; humans; cancer-associated fibroblasts; human
Journal Title: Cancer Research
Volume: 83
Issue: 10
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2023-05-15
Start Page: 1596
End Page: 1610
Language: English
DOI: 10.1158/0008-5472.Can-22-2316
PUBMED: 36912618
PROVIDER: scopus
PMCID: PMC10658995
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Craig B. Thompson -- Source: Scopus
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MSK Authors
  1. Scott W Lowe
    250 Lowe
  2. Craig Bernie Thompson
    155 Thompson
  3. Kaloyan M Tsanov
    8 Tsanov
  4. Francesco Cimino
    3 Cimino
  5. Charles Peter Ng
    3 Ng