title: Stromal cues regulate the pancreatic cancer epigenome and metabolome.
abstract: A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular "AND-gate" such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Mara H
authors.initials: MH
authors.lastname: Sherman
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Tiffany W
authors.initials: TW
authors.lastname: Tseng
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors.forename: Cristovao M
authors.initials: CM
authors.lastname: Sousa
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Sihao
authors.initials: S
authors.lastname: Liu
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Truitt
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Nanhai
authors.initials: N
authors.lastname: He
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.affiliation: Storr Liver Centre, Westmead Millennium Institute, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Mathias
authors.initials: M
authors.lastname: Leblanc
authors.affiliation: Department of Medicine/Hematology and Oncology, University of California, San Francisco, CA 94143.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.affiliation: Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Department of Radiation Oncology, New York University School of Medicine, New York, NY 10016.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu downes@salk.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu downes@salk.edu.|Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000107:Acetylation; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism; D004734:Energy Metabolism; D004742:Enhancer Elements, Genetic; D005347:Fibroblasts / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D042421:Histone Code; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D055442:Metabolome; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D058954:Pancreatic Stellate Cells / Q000502:physiology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D017154:Stromal Cells / Q000502:physiology*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000502:physiology*; D000092468:Bromodomain Containing Proteins
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins
keywords: BRD2; cancer metabolism; histone acetylation; pancreatic ductal adenocarcinoma; tumor microenvironment