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

School of Medicine

Research output: Contribution to journal › Article › peer-review

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 (US)
Pages (from-to)	497-505
Number of pages	9
Journal	Nature medicine
Volume	22
Issue number	5
DOIs	https://doi.org/10.1038/nm.4082
State	Published - May 1 2016

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1038/nm.4082

Fingerprint Dive into the research topics of 'Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression'. Together they form a unique fingerprint.

Cite this

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

Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. / Laklai, Hanane; Miroshnikova, Yekaterina A.; Pickup, Michael W.; Collisson, Eric A.; Kim, Grace E.; Barrett, Alex S.; Hill, Ryan C.; Lakins, Johnathon N.; Schlaepfer, David D.; Mouw, Janna K.; LeBleu, Valerie S.; Roy, Nilotpal; Novitskiy, Sergey V.; Johansen, Julia S.; Poli, Valeria; Kalluri, Raghu; Iacobuzio-Donahue, Christine A.; Wood, Laura D.; Hebrok, Matthias; Hansen, Kirk; Moses, Harold L.; Weaver, Valerie M.

In: Nature medicine, Vol. 22, No. 5, 01.05.2016, p. 497-505.

Research output: Contribution to journal › Article › peer-review

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

Laklai, Hanane ; Miroshnikova, Yekaterina A. ; Pickup, Michael W. ; Collisson, Eric A. ; Kim, Grace E. ; Barrett, Alex S. ; Hill, Ryan C. ; Lakins, Johnathon N. ; Schlaepfer, David D. ; Mouw, Janna K. ; LeBleu, Valerie S. ; Roy, Nilotpal ; Novitskiy, Sergey V. ; Johansen, Julia S. ; Poli, Valeria ; Kalluri, Raghu ; Iacobuzio-Donahue, Christine A. ; Wood, Laura D. ; Hebrok, Matthias ; Hansen, Kirk ; Moses, Harold L. ; Weaver, Valerie M. / Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. In: Nature medicine. 2016 ; Vol. 22, No. 5. pp. 497-505.

@article{1f69618221534d43a35bb9bcd7b225a5,

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.}",

note = "Funding Information: 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. and 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.).",

year = "2016",

month = may,

day = "1",

doi = "10.1038/nm.4082",

language = "English (US)",

volume = "22",

pages = "497--505",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "5",

}

TY - JOUR

T1 - Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

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.

N1 - Funding Information: 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. and 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.).

PY - 2016/5/1

Y1 - 2016/5/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84964317478&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964317478&partnerID=8YFLogxK

U2 - 10.1038/nm.4082

DO - 10.1038/nm.4082

M3 - Article

C2 - 27089513

AN - SCOPUS:84964317478

VL - 22

SP - 497

EP - 505

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 5

ER -