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

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; Julia S. Johansen; Valeria Poli; Raghu Kalluri; Christine A Iacobuzio-Donahue; Laura D. Wood; Matthias Hebrok; Kirk Hansen; Harold L. Moses; Valerie M Weaver

doi:10.1038/nm.4082

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

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, Julia S. Johansen, Valeria Poli, Raghu Kalluri, Christine A Iacobuzio-Donahue, Laura D. Wood, Matthias Hebrok, Kirk HansenHarold L. Moses, Valerie M Weaver

Department of Clinical Medicine

251 Citations (Scopus)

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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.

Original language	English
Journal	Nature Medicine
Volume	22
Issue number	5
Pages (from-to)	497-505
Number of pages	9
ISSN	1078-8956
DOIs	https://doi.org/10.1038/nm.4082
Publication status	Published - May 2016

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Laklai, H., Miroshnikova, Y. A., Pickup, M. W., Collisson, E. A., Kim, G. E., Barrett, A. S., Hill, R. C., Lakins, J. N., Schlaepfer, D. D., Mouw, J. K., LeBleu, V. S., Roy, N., Novitskiy, S. V., Johansen, J. S., Poli, V., Kalluri, R., Iacobuzio-Donahue, C. A., Wood, L. D., Hebrok, M., ... Weaver, V. M. (2016). Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nature Medicine, 22(5), 497-505. https://doi.org/10.1038/nm.4082

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 2016, 'Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression', Nature Medicine, vol. 22, no. 5, pp. 497-505. https://doi.org/10.1038/nm.4082

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title = "Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression",

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.",

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

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AU - Laklai, Hanane

AU - Miroshnikova, Yekaterina A.

AU - Pickup, Michael W.

AU - Collisson, Eric A.

AU - Kim, Grace E.

AU - Barrett, Alex S.

AU - Hill, Ryan C.

AU - Lakins, Johnathon N

AU - Schlaepfer, David D.

AU - Mouw, Janna K.

AU - LeBleu, Valerie S.

AU - Roy, Nilotpal

AU - Novitskiy, Sergey V.

AU - Johansen, Julia S.

AU - Poli, Valeria

AU - Kalluri, Raghu

AU - Iacobuzio-Donahue, Christine A

AU - Wood, Laura D.

AU - Hebrok, Matthias

AU - Hansen, Kirk

AU - Moses, Harold L.

AU - Weaver, Valerie M

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N2 - 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.

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

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