title: Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.
abstract: Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Hanane
authors.initials: H
authors.lastname: Laklai
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Yekaterina A
authors.initials: YA
authors.lastname: Miroshnikova
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pickup
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, Colorado, USA.
authors.forename: Alex S
authors.initials: AS
authors.lastname: Barrett
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, Colorado, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Hill
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Johnathon N
authors.initials: JN
authors.lastname: Lakins
authors.affiliation: Department of Reproductive Medicine, University of California, San Diego Moores Cancer Center, La Jolla, California, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Schlaepfer
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Janna K
authors.initials: JK
authors.lastname: Mouw
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: LeBleu
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Nilotpal
authors.initials: N
authors.lastname: Roy
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Novitskiy
authors.affiliation: Department of Oncology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Johansen
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
authors.forename: Valeria
authors.identifier: 0000-0002-3739-3966
authors.initials: V
authors.lastname: Poli
authors.affiliation: Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.affiliation: Department of Pathology, David Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Christine A
authors.identifier: 0000-0002-4672-3023
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: Gastrointestinal and Liver Pathology Department, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, Colorado, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Hansen
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
authors.affiliation: Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.|Department of Anatomy, University of California, San Francisco, San Francisco, California, USA.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.|Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002853:Chromatography, Liquid; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005838:Genotype; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism*; D051379:Mice; D018625:Microscopy, Atomic Force; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D040901:Proteomics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics; D015996:Survival Rate; D053719:Tandem Mass Spectrometry; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D039641:Integrin beta Chains; C497796:SMAD4 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051901:Smad4 Protein; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta; D003094:Collagen; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)