title: Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts.
abstract: Although histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs, thus far, they have been unsuccessful in early phase clinical trials for pancreatic ductal adenocarcinoma (PDAC). One potential reason for their poor efficacy is the tumor stroma, where cancer-associated fibroblasts (CAFs) are a prominent cell type and a source of resistance to cancer therapies. Here, we demonstrate that stromal fibroblasts contribute to the poor efficacy of HDACi's in PDAC. HDACi-treated fibroblasts show increased biological aggressiveness and are characterized by increased secretion of pro-inflammatory tumor-supportive cytokines and chemokines. We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes specifically in CAFs and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions. Pharmacologic inhibition of pathways upstream of AP-1 suppresses the HDACi-induced inflammatory gene expression and tumor-supportive responses in fibroblasts. Our findings demonstrate that the combination of HDACi's with chemical inhibitors of the AP-1 signaling pathway attenuate the inflammatory phenotype of fibroblasts and may improve the efficacy of HDACi in PDAC and, potentially, in other solid tumors rich in stroma.
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Nguyen
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Irmina A
authors.initials: IA
authors.lastname: Elliott
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Nanping
authors.initials: N
authors.lastname: Wu
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Matsumura
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Vogelauer
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Narsis
authors.initials: N
authors.lastname: Attar
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Dann
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Razmik
authors.initials: R
authors.lastname: Ghukasyan
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Toste
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Sanjeet G
authors.initials: SG
authors.lastname: Patel
authors.affiliation: Department of Surgery, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Williams
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Luyi
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Caius
authors.initials: C
authors.lastname: Radu
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Siavash K
authors.initials: SK
authors.lastname: Kurdistani
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.|Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Donahue
mesh_terms: D000818:Animals; D015153:Blotting, Western; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects* / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors
keywords: AP-1; SAHA; cancer-associated fibroblasts; histone deacetylase inhibitor; pancreatic cancer