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Nat Med. 2016 May;22(5):497-505. doi: 10.1038/nm.4082. Epub 2016 Apr 18.

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

Author information

1
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
2
Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
3
Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
4
Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, Colorado, USA.
5
Department of Reproductive Medicine, University of California, San Diego Moores Cancer Center, La Jolla, California, USA.
6
Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
7
Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
8
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
9
Department of Oncology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
10
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
11
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.
12
Gastrointestinal and Liver Pathology Department, Johns Hopkins University, Baltimore, Maryland, USA.
13
Department of Anatomy, University of California, San Francisco, San Francisco, California, USA.
14
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
15
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA.
16
Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.

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.

PMID:
27089513
PMCID:
PMC4860133
DOI:
10.1038/nm.4082
[Indexed for MEDLINE]
Free PMC Article

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