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

Nature Medicine volume 22, pages 497–505 (2016)Cite this article

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An Author Correction to this article was published on 28 November 2023

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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.

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Figure 1: Tissue tension and collagen thickness linked to PDAC prognosis.
Figure 2: PDAC genotype tunes epithelial tension to regulate fibrosis.
Figure 3: JAK-STAT3 signaling drives ECM remodeling and stiffening.
Figure 4: Tumor cell tension accelerates PDAC progression in mice.
Figure 5: STAT3 induces fibrosis and accelerates PDAC.
Figure 6: STAT3 enhances epithelial contractility to induce PDAC fibrosis and aggression.

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Acknowledgements

We thank M. Dembo for the LIBTRC 2.0 traction force software. We thank M. Tempero for helpful discussions, and L. Korets and N. Korets for animal handling and tissue processing. This work was supported by US National Institutes of Health NCI grants U01 CA151925-01 (V.M.W., H.L.M. and R.K.), R33 CA183685-01 (V.M.W. and K.H.), R01 CA138818-01A1 (V.M.W.), U54CA143836-01 (V.M.W.), CA102310 (D.D.S.), R01CA178015-02 (E.A.C.), R01 CA172045 (R.N. and M.H.), T32CA108462 (M.W.P.), F31CA180422 (Y.A.M.), the Pancreatic Cancer Action Network–AACR Innovative Grant 30-60-25-WEAV (V.M.W.), NSF GRFP 1144247 (Y.A.M.) and NIH TL1 TR001081 (A.S.B.).

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Authors and Affiliations

  1. Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, California, USA

    Hanane Laklai, Yekaterina A Miroshnikova, Michael W Pickup, Johnathon N Lakins, Janna K Mouw & Valerie M Weaver

  2. Department of Medicine, University of California, San Francisco, San Francisco, California, USA

    Eric A Collisson

  3. Department of Pathology, University of California, San Francisco, San Francisco, California, USA

    Grace E Kim

  4. Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, Aurora, Colorado, USA

    Alex S Barrett, Ryan C Hill & Kirk Hansen

  5. Department of Reproductive Medicine, University of California, San Diego Moores Cancer Center, La Jolla, California, USA

    David D Schlaepfer

  6. Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Valerie S LeBleu & Raghu Kalluri

  7. Department of Medicine, Diabetes Center, University of California, San Francisco, San Francisco, California, USA

    Nilotpal Roy & Matthias Hebrok

  8. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Sergey V Novitskiy & Harold L Moses

  9. Department of Oncology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark

    Julia S Johansen

  10. Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy

    Valeria Poli

  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

    Christine A Iacobuzio-Donahue

  12. Gastrointestinal and Liver Pathology Department, Johns Hopkins University, Baltimore, Maryland, USA

    Laura D Wood

  13. Department of Anatomy, University of California, San Francisco, San Francisco, California, USA

    Valerie M Weaver

  14. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA

    Valerie M Weaver

  15. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA

    Valerie M Weaver

  16. Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA

    Valerie M Weaver

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  1. Hanane Laklai
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Contributions

V.M.W. conceived the project, and designed and directed all of the studies with input from all authors. H.L. conducted transgenic mouse experiments and treatments. H.L. performed histology, immunofluorescence and image analysis on mice and human samples, conducted experiments with the PA hydrogels, and performed 3D collagen and soft agar assays, cytokine arrays, immunoblotting and related analyses. H.L. and Y.A.M. performed AFM imaging and analysis. Y.A.M. performed TFM and two-photon imaging and analysis. H.L. and M.W.P. conducted orthotopic xenograft experiments. M.W.P. performed RT-PCR and bioinformatics. S.V.N. and M.W.P. performed flow sorting. J.N.L. designed and constructed expression constructs and the V737N transgenic mouse. E.A.C. and G.E.K. aided with pathological pancreatic cancer scoring of transgenic mice and human samples. J.S.J. and E.A.C. collected human samples from short- and long-survival patients and aided in the interpretation of the data. C.A.I.-D. and L.D.W. collected human samples from wild-type and mutant SMAD4 patients and aided in the interpretation of the data. R.K., V.S.L., M.H. and N.R. provided KPC pancreatic tissues. V.P. provided Stat3 flox/flox and constitutively active STAT3C transgenic mice. A.S.B., R.C.H. and K.H. performed LC-MS-MS and LC-SRM proteomic analysis. D.D.S. provided Ptk2 inhibitor PND-1186. H.L.M. designed and provided KTC transgenic mouse, provided KC mice and aided in interpretation of data. V.M.W., H.L., Y.A.M., J.K.M. and M.W.P. wrote the manuscript with input from all authors.

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Correspondence to Valerie M Weaver.

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Laklai, H., Miroshnikova, Y., Pickup, M. et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med 22, 497–505 (2016). https://doi.org/10.1038/nm.4082

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