{"doi":"10.1101/2023.09.12.557260","title":"Inhibiting Stromal Class I HDACs Curbs Pancreatic Cancer Progression","abstract":"Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":411435,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":232495,"name":"Tae Gyu Oh","orcid":"0000-0002-2756-3546","position":1,"is_corresponding":false},{"id":288513,"name":"Nasun Hah","orcid":"0000-0003-1509-2799","position":2,"is_corresponding":false},{"id":266832,"name":"Hervé Tiriac","orcid":"0000-0001-5039-6750","position":3,"is_corresponding":false},{"id":364414,"name":"Yu Shi","orcid":"0000-0001-6742-9598","position":4,"is_corresponding":false},{"id":860816,"name":"Morgan Truitt","orcid":"0000-0001-7012-1228","position":5,"is_corresponding":false},{"id":308161,"name":"Corina E. 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