Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

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  • nihms917788

    Accepted author manuscript, 5.25 MB, PDF document

  • Hanane Laklai
  • Yekaterina A. Miroshnikova
  • Michael W. Pickup
  • Eric A. Collisson
  • Grace E. Kim
  • Alex S. Barrett
  • Ryan C. Hill
  • Johnathon N Lakins
  • David D. Schlaepfer
  • Janna K. Mouw
  • Valerie S. LeBleu
  • Nilotpal Roy
  • Sergey V. Novitskiy
  • Valeria Poli
  • Raghu Kalluri
  • Christine A Iacobuzio-Donahue
  • Laura D. Wood
  • Matthias Hebrok
  • Kirk Hansen
  • Harold L. Moses
  • Valerie M Weaver

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.

Original languageEnglish
JournalNature Medicine
Volume22
Issue number5
Pages (from-to)497-505
Number of pages9
ISSN1078-8956
DOIs
Publication statusPublished - May 2016

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