[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Subjects

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

This article has been updated

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

Change history

References

  1. Chauhan, V.P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013).

    Article  PubMed  Google Scholar 

  2. Swartz, M.A. & Lund, A.W. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat. Rev. Cancer 12, 210–219 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Yu, M. & Tannock, I.F. Targeting tumor architecture to favor drug penetration: a new weapon to combat chemoresistance in pancreatic cancer? Cancer Cell 21, 327–329 (2012).

    Article  CAS  PubMed  Google Scholar 

  4. Provenzano, P.P. & Hingorani, S.R. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br. J. Cancer 108, 1–8 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Olive, K.P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Provenzano, P.P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rosow, D.E. et al. Sonic Hedgehog in pancreatic cancer: from bench to bedside, then back to the bench. Surgery 152 (suppl. 1), S19–S32 (2012).

    Article  PubMed  Google Scholar 

  8. Özdemir, B.C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Rhim, A.D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jain, R.K., Martin, J.D. & Stylianopoulos, T. The role of mechanical forces in tumor growth and therapy. Annu. Rev. Biomed. Eng. 16, 321–346 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Neesse, A. et al. Stromal biology and therapy in pancreatic cancer. Gut 60, 861–868 (2011).

    Article  PubMed  Google Scholar 

  12. Stromnes, I.M., DelGiorno, K.E., Greenberg, P.D. & Hingorani, S.R. Stromal reengineering to treat pancreas cancer. Carcinogenesis 35, 1451–1460 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cheung, K.J., Gabrielson, E., Werb, Z. & Ewald, A.J. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155, 1639–1651 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hoadley, K.A. et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158, 929–944 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

  16. Sugimoto, H., Mundel, T.M., Kieran, M.W. & Kalluri, R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol. Ther. 5, 1640–1646 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Wang, Y., You, M. & Wang, Y. Alternative splicing of the K-ras gene in mouse tissues and cell lines. Exp. Lung Res. 27, 255–267 (2001).

    Article  PubMed  Google Scholar 

  18. Paszek, M.J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Samuel, M.S. et al. Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth. Cancer Cell 19, 776–791 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Iacobuzio-Donahue, C.A. et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J. Clin. Oncol. 27, 1806–1813 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Whittle, M.C. et al. RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell 161, 1345–1360 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ijichi, H. et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expression. Genes Dev. 20, 3147–3160 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Collisson, E.A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Moffitt, R.A. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kabashima, A. et al. Side population of pancreatic cancer cells predominates in TGF-β-mediated epithelial to mesenchymal transition and invasion. Int. J. Cancer 124, 2771–2779 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Dangi-Garimella, S. et al. Three-dimensional collagen I promotes gemcitabine resistance in pancreatic cancer through MT1-MMP-mediated expression of HMGA2. Cancer Res. 71, 1019–1028 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Erkan, M. et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 6, 1155–1161 (2008).

    Article  PubMed  Google Scholar 

  28. Sinn, M. et al. α-smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study. Br. J. Cancer 111, 1917–1923 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bever, K.M. et al. The prognostic value of stroma in pancreatic cancer in patients receiving adjuvant therapy. HPB 17, 292–298 (2015).

    Article  PubMed  Google Scholar 

  30. Wang, W.Q. et al. Intratumoral α-SMA enhances the prognostic potency of CD34 associated with maintenance of microvessel integrity in hepatocellular carcinoma and pancreatic cancer. PLoS One 8, e71189 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rath, N. & Olson, M.F. Rho-associated kinases in tumorigenesis: re-considering ROCK inhibition for cancer therapy. EMBO Rep. 13, 900–908 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schultz, N.A. et al. MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma. Mod. Pathol. 25, 1609–1622 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Pérez-Mancera, P.A., Guerra, C., Barbacid, M. & Tuveson, D.A. What we have learned about pancreatic cancer from mouse models. Gastroenterology 142, 1079–1092 (2012).

    Article  PubMed  Google Scholar 

  34. Macias, M.J., Martin-Malpartida, P. & Massagué, J. Structural determinants of Smad function in TGF-β signaling. Trends Biochem. Sci. 40, 296–308 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shi, Y. & Massagué, J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Yachida, S. et al. Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin. Cancer Res. 18, 6339–6347 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hingorani, S.R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Hingorani, S.R. et al. Trp53 R172H and Kras G12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Blackford, A. et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin. Cancer Res. 15, 4674–4679 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sanz-Moreno, V. et al. ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 20, 229–245 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Fukuda, A. et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19, 441–455 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lesina, M. et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Nagathihalli, N.S. et al. Signal transducer and activator of transcription 3, mediated remodeling of the tumor microenvironment results in enhanced tumor drug delivery in a mouse model of pancreatic cancer. Gastroenterology 149, 1932–1943 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Ijichi, H. et al. Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma. J. Clin. Invest. 121, 4106–4117 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schrader, J. et al. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 53, 1192–1205 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Mouw, J.K. et al. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat. Med. 20, 360–367 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li, R. et al. Activation of integrin αIIbβ3 by modulation of transmembrane helix associations. Science 300, 795–798 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Barbieri, I. et al. Constitutively active Stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of Cten. Cancer Res. 70, 2558–2567 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Alonzi, T. et al. Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation in the liver. Mol. Cell. Biol. 21, 1621–1632 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Luna, A. et al. Multiparametric MR imaging in abdominal malignancies. Magn. Reson. Imaging Clin. N. Am. 24, 157–186 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Chauhan, V.P. et al. Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. Cancer Cell 26, 14–15 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Herreros-Villanueva, M. et al. SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells. Oncogenesis 2, e61 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shao, D.D. et al. KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 158, 171–184 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Jiang, J. et al. MiR-1181 inhibits stem cell-like phenotypes and suppresses SOX2 and STAT3 in human pancreatic cancer. Cancer Lett. 356 2 Pt B, 962–970 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. Yimlamai, D. et al. Hippo pathway activity influences liver cell fate. Cell 157, 1324–1338 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kohler, I. et al. Detailed analysis of epithelial-mesenchymal transition and tumor budding identifies predictors of long-term survival in pancreatic ductal adenocarcinoma. J. Gastroenterol. Hepatol. 30 (suppl. 1), 78–84 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Paron, I. et al. Tenascin-C enhances pancreatic cancer cell growth and motility and affects cell adhesion through activation of the integrin pathway. PLoS ONE 6, e21684 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Esposito, I. et al. Tenascin C and annexin II expression in the process of pancreatic carcinogenesis. J. Pathol. 208, 673–685 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Hill, R.C., Calle, E.A., Dzieciatkowska, M., Niklason, L.E. & Hansen, K.C. Quantification of extracellular matrix proteins from a rat lung scaffold to provide a molecular readout for tissue engineering. Mol. Cell. Proteomics 14, 961–973 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lopez, J.I., Kang, I., You, W.-K., McDonald, D.M. & Weaver, V.M. In situ force mapping of mammary gland transformation. Integr. Biol. (Camb) 3, 910–921 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Pickup, M.W. et al. Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas. Cancer Res. 73, 5336–5346 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bullen, A., Friedman, R.S. & Krummel, M.F. Two-photon imaging of the immune system: a custom technology platform for high-speed, multicolor tissue imaging of immune responses. Curr. Top. Microbiol. Immunol. 334, 1–29 (2009).

    PubMed  Google Scholar 

  64. Aguirre, A.J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Damiano, L. et al. Oncogenic targeting of BRM drives malignancy through C/EBPβ-dependent induction of α5 integrin. Oncogene 33, 2441–2453 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Reinhart-King, C.A., Dembo, M. & Hammer, D.A. Endothelial cell traction forces on RGD-derivatized polyacrylamide substrata. Langmuir 19, 1573–1579 (2003).

    Article  CAS  Google Scholar 

  67. Lakins, J.N., Chin, A.R. & Weaver, V.M. Methods Mol. Biol. 916, 317–350 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Paszek, M.J. et al. The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Nature 511, 319–325 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mann, M.D., Crouse, D.A. & Prentice, E.D. Appropriate animal numbers in biomedical research in light of animal welfare considerations. Lab. Animal Sci. 41, 6–14 (1991).

    CAS  Google Scholar 

Download references

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.).

Author information

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

Authors
  1. Hanane Laklai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yekaterina A Miroshnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael W Pickup
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric A Collisson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Grace E Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alex S Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ryan C Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Johnathon N Lakins
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David D Schlaepfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Janna K Mouw
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Valerie S LeBleu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nilotpal Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sergey V Novitskiy
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Julia S Johansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Valeria Poli
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Raghu Kalluri
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Christine A Iacobuzio-Donahue
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Laura D Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Matthias Hebrok
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Kirk Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Harold L Moses
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Valerie M Weaver
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Valerie M Weaver.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 and Supplementary Tables 1–2 (PDF 7903 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4082

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer