TY - JOUR
T1 - Hypoxia Potentiates the Inflammatory Fibroblast Phenotype Promoted by Pancreatic Cancer Cell-Derived Cytokines
AU - Schwörer, Simon
AU - Cimino, Francesco V.
AU - Ros, Manon
AU - Tsanov, Kaloyan M.
AU - Ng, Charles
AU - Lowe, Scott W.
AU - Carmona-Fontaine, Carlos
AU - Thompson, Craig B.
N1 - Funding Information:
Theauthors thankthe membersoftheThompsonlaboratoryfor helpful discussions. The authors are thankful to Tullia Lindsten for help with planning of and protocol preparation for mouse experiments, and to Natalya N. Pavlova for help with GMAP. They also thank Elisa De Stanchina, Inna Kudos, and Janelle Simon for help with orthotopic organoid injections into the pancreas, and Wenfei Kang and Eric Rosiek of the MSKCC Molecular Cytology Core for help with IF staining, microscopy and image analysis. S. Schworer received support from the NCI (5K99CA259224) and the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center at MSKCC. S. Schworer is also supported by a Hirshberg Foundation Seed Grant, the AGAResearch Foundation’s Caroline Craig Augustyn & Damian Augustyn Award in Digestive Cancer, and an ACS-IRG Pilot Grant from the University of Chicago Comprehensive Cancer Center. K.M. Tsanov was supported by the Jane Coffin Childs Memorial Fund for Medical Research and a Shulamit Katzman Endowed Postdoctoral Research Fellowship. This work was supported by MSKCC’s David Rubenstein Center for Pancreatic Research PilotProject (to S.W. Lowe) and NIHgrant P01CA013106 (to S.W. Lowe).S.W. Lowe is theGeoffrey Beene Chairfor Cancer Biology atMSKCC. C. Carmona-Fontaine receives support from the NCI at the NIH (DP2 CA250005), the American Cancer Society (RSG-21-179-01-TBE), and the Pew Charitable Trust (00034121). C.B. Thompson was supported by the NCI (R01CA201318). This work used core facilities at MSKCC that were supported by the cancer center support grant (P30CA008748).
Funding Information:
S. Schworer reports grants from NCI, Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, Hirshberg Foundation, AGA Research Foundation, and American Cancer Society during the conduct of the study. K.M. Tsanov reports other support from Jane Coffin Childs Memorial Fund for Medical Research and Shulamit Katzman Endowed Postdoctoral Research Fellowship, and grants from MSKCC David Rubenstein Center for Pancreatic Research Pilot Project during the conduct of the study. S.W. Lowe reports nothing directly related to this work; however, indirectly, S.W. Lowe is a consultant for and has equity in Oric Pharmaceuticals, Blueprint Medicines, Mirimus Inc., Senecea Therapeutics, Faeth Therapeutics, and PMV Pharmaceuticals. C.B. Thompson reports grants from NCI during the conduct of the study and personal fees from Agios, Charles River Laboratories, and Regeneron outside the submitted work. No disclosures were reported by the other authors.
Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/5/15
Y1 - 2023/5/15
N2 - 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 HIF1a-dependent fashion. Furthermore, HIF1a 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 HIF1a as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC.
AB - 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 HIF1a-dependent fashion. Furthermore, HIF1a 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 HIF1a as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC.
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UR - http://www.scopus.com/inward/citedby.url?scp=85159168752&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-22-2316
DO - 10.1158/0008-5472.CAN-22-2316
M3 - Article
C2 - 36912618
AN - SCOPUS:85159168752
SN - 0008-5472
VL - 83
SP - 1596
EP - 1610
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -