{"doi":"10.1101/2022.07.26.501639","title":"Hypoxia potentiates the inflammatory fibroblast phenotype promoted by pancreatic cancer cell-derived cytokines","abstract":"Abstract Cancer-associated fibroblasts (CAFs) are a major cell type in the stroma of solid tumors and can exert both tumor-promoting and tumor-restraining functions. This functional heterogeneity is correlated with the existence of transcriptionally distinct subpopulations of CAFs. CAF heterogeneity is observed in pancreatic ductal adenocarcinoma (PDAC), a tumor characterized by a remarkably dense and hypoxic stroma that features tumor-restraining myofibroblastic CAFs (myCAFs) and tumor-supporting inflammatory CAFs (iCAFs). 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 display a hypoxic gene expression and biochemical profile and are enriched in hypoxic regions of PDAC tumors. Hypoxia leads fibroblasts to acquire an inflammatory gene expression signature and synergizes with cancer cell-derived cytokines to promote an iCAF phenotype in a HIF-1α dependent fashion. Furthermore, we show that HIF-1α stabilization is sufficient to induce an iCAF phenotype in stromal cells introduced into PDAC organoid co-cultures and to promote PDAC tumor growth. These findings indicate hypoxia-induced HIF-1α as a regulator of CAF heterogeneity and promoter of tumor progression in PDAC.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":298328,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9504,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":987302,"name":"Manon Ros","orcid":"0000-0001-7878-3613","position":1,"is_corresponding":false},{"id":319946,"name":"Kaloyan M. Tsanov","orcid":"0000-0001-9007-4844","position":2,"is_corresponding":false},{"id":987303,"name":"Francesco V. Cimino","orcid":"0000-0003-1005-219X","position":3,"is_corresponding":false},{"id":218307,"name":"Scott W. Lowe","orcid":"0000-0002-5284-9650","position":4,"is_corresponding":false},{"id":819311,"name":"Carlos Carmona‐Fontaine","orcid":"0000-0002-5238-6852","position":5,"is_corresponding":false},{"id":611838,"name":"Craig B. Thompson","orcid":"0000-0003-3580-2751","position":6,"is_corresponding":false},{"id":625756,"name":"Simon Schwörer","orcid":"0000-0002-2972-9917","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T00:31:36.269611Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}