title: Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation.
abstract: Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a "ductal-like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA.
authors: Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA;
authors: Nilotpal
authors: N
authors: Roy
authors: Department of Medicine/Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA;
authors: Shivani
authors: S
authors: Malik
authors: Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA;
authors: Karina E
authors: KE
authors: Villanueva
authors: Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA;
authors: Atsushi
authors: A
authors: Urano
authors: Department of Medicine/Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA;
authors: Xinyuan
authors: X
authors: Lu
authors: II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar der Technischen Universität München, 81675 Munich, Germany;
authors: Guido
authors: G
authors: Von Figura
authors: Department of Pathology, University of California at San Francisco, San Francisco, California 94143, USA;
authors: E Scott
authors: ES
authors: Seeley
authors: Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
authors: David W
authors: DW
authors: Dawson
authors: Department of Medicine/Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA;
authors: Eric A
authors: EA
authors: Collisson
authors: Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA; mhebrok@diabetes.ucsf.edu.
authors: Matthias
authors: M
authors: Hebrok
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000503:physiopathology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D009687:Nuclear Proteins; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D014157:Transcription Factors; D014230:Triazoles; C513194:Smarca4 protein, mouse; D004265:DNA Helicases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Brg1; EMT; IPMN; Kras; dedifferentiation; pancreatic cancer