title: Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment.
abstract: OBJECTIVE
  The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC.
  
  
  METHODS
  In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC.
  
  
  RESULTS
  In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models.
  
  
  CONCLUSIONS
  Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Clin Cancer Res; 22(16); 4259-70. ©2016 AACR.
authors.affiliation: Departments of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China. Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Yinshi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sabikun
authors.initials: S
authors.lastname: Nahar
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Nakagawa
authors.affiliation: Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernandez-Barrena
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Mertz
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bryant
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Curtis E
authors.initials: CE
authors.lastname: Adams
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Kate N
authors.initials: KN
authors.lastname: Von Alt
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chang
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Conery
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Charlie
authors.initials: C
authors.lastname: Hatton
authors.affiliation: Constellation Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sims
authors.affiliation: Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: Departments of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China. Departments of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiatong University School of Medicine, Shanghai, P.R. China.
authors.forename: Xingpeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Lillemoe
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Del Castillo
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Warshaw
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. aliss@mgh.harvard.edu sarah.thayer@unmc.edu.
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Thayer
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. aliss@mgh.harvard.edu sarah.thayer@unmc.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Liss
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D016259:Genes, myc; D053823:Hedgehog Proteins / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden; D059016:Tumor Microenvironment / Q000235:genetics; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D016601:RNA-Binding Proteins; C509239:SHH protein, human; D000071676:Zinc Finger Protein GLI1