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

Laklai H, Miroshnikova YA, Pickup MW, Collisson EA, Kim GE, Barrett AS, Hill RC, Lakins JN, Schlaepfer DD, Mouw JK, LeBleu VS, Roy N, Novitskiy SV, Johansen JS, Poli V, Kalluri R, Iacobuzio-Donahue CA, Wood LD, Hebrok M, Hansen K, Moses HL, Weaver VM
Nat Med. 2016 22 (5): 497-505

PMID: 27089513 · PMCID: PMC4860133 · DOI:10.1038/nm.4082

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.

MeSH Terms (26)

Animals Carcinoma, Pancreatic Ductal Chromatography, Liquid Collagen Disease Models, Animal Disease Progression Extracellular Matrix Fibrosis Genotype Humans Integrin beta Chains Mice Microscopy, Atomic Force Mutation Pancreatic Neoplasms Prognosis Proteomics Proto-Oncogene Proteins p21(ras) Real-Time Polymerase Chain Reaction Signal Transduction Smad4 Protein STAT3 Transcription Factor Survival Rate Tandem Mass Spectrometry Transforming Growth Factor beta Tumor Microenvironment

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