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Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.
Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W; Collisson, Eric A; Kim, Grace E; Barrett, Alex S; Hill, Ryan C; Lakins, Johnathon N; Schlaepfer, David D; Mouw, Janna K; LeBleu, Valerie S; Roy, Nilotpal; Novitskiy, Sergey V; Johansen, Julia S; Poli, Valeria; Kalluri, Raghu; Iacobuzio-Donahue, Christine A; Wood, Laura D; Hebrok, Matthias; Hansen, Kirk; Moses, Harold L; Weaver, Valerie M.
Afiliación
  • Laklai H; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Miroshnikova YA; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Pickup MW; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Collisson EA; Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Kim GE; Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
  • Barrett AS; Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, Colorado, USA.
  • Hill RC; Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, Colorado, USA.
  • Lakins JN; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Schlaepfer DD; Department of Reproductive Medicine, University of California, San Diego Moores Cancer Center, La Jolla, California, USA.
  • Mouw JK; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
  • LeBleu VS; Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
  • Roy N; Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Novitskiy SV; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • Johansen JS; Department of Oncology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
  • Poli V; Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
  • Kalluri R; Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
  • Iacobuzio-Donahue CA; 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.
  • Wood LD; Gastrointestinal and Liver Pathology Department, Johns Hopkins University, Baltimore, Maryland, USA.
  • Hebrok M; Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Hansen K; Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, Colorado, USA.
  • Moses HL; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • Weaver VM; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
Nat Med ; 22(5): 497-505, 2016 05.
Article en En | MEDLINE | ID: mdl-27089513
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-ß (TGF-ß) 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-ß signaling and elevated ß1-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-ß 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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Factor de Crecimiento Transformador beta / Carcinoma Ductal Pancreático / Cadenas beta de Integrinas / Factor de Transcripción STAT3 / Matriz Extracelular Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Factor de Crecimiento Transformador beta / Carcinoma Ductal Pancreático / Cadenas beta de Integrinas / Factor de Transcripción STAT3 / Matriz Extracelular Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos