Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation

Nilotpal Roy; Shivani Malik; Karina E. Villanueva; Atsushi Urano; Xinyuan Lu; Guido Von Figura; E. Scott Seeley; David W. Dawson; Eric A. Collisson; Matthias Hebrok

doi:10.1101/gad.256628.114

Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation

¹Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA;
²Department of Medicine/Hematology and Oncology, University of California at San Francisco, San Francisco, California 94143, USA;
³II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar der Technischen Universität München, 81675 Munich, Germany;
⁴Department of Pathology, University of California at San Francisco, San Francisco, California 94143, USA;
⁵Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA

Corresponding author: mhebrok{at}diabetes.ucsf.edu

↵6 These authors contributed equally to this work.

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.

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Footnotes

Supplemental material is available for this article.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.256628.114.

Received November 30, 2014.
Accepted February 13, 2015.

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