TGF-β Tumor Suppression through a Lethal EMT

被引：641

作者：

David, Charles J. ^{[1
]}

Huang, Yun-Han ^{[1
]}

Chen, Mo ^{[3
]}

Su, Jie ^{[1
]}

Zou, Yilong ^{[1
]}

Bardeesy, Nabeel ^{[4
]}

Iacobuzio-Donahue, Christine A. ^{[2
]}

Massague, Joan ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[3] Rockefeller Univ, New York, NY 10065 USA

[4] Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02114 USA

来源：

CELL | 2016年 / 164卷 / 05期

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; LINEAGE-SURVIVAL ONCOGENES; GROWTH-FACTOR; TRANSCRIPTION FACTOR; PANCREATIC-CANCER; ENHANCED EXPRESSION; SELF-RENEWAL; STEM-CELLS; SOX4; KLF5;

D O I：

10.1016/j.cell.2016.01.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

TGF-beta signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-beta mediator Smad4. We show that TGF-beta induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-beta-sensitive PDA cells, EMT becomes lethal by converting TGF-beta-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-beta. TGF-beta-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-beta tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.

引用

页码：1015 / 1030

页数：16

共 60 条

[1]

Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma [J].

Aguirre, AJ ;

Bardeesy, N ;

Sinha, M ;

Lopez, L ;

Tuveson, DA ;

Horner, J ;

Redston, MS ;

DePinho, RA .

GENES & DEVELOPMENT, 2003, 17 (24) :3112-3126

[2]

Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer [J].

Bardeesy, Nabeel ;

Cheng, Kuang-hung ;

Berger, Justin H. ;

Chu, Gerald C. ;

Pahler, Jessica ;

Olson, Peter ;

Hezel, Aram F. ;

Horner, James ;

Lauwers, Gregory Y. ;

Hanahan, Douglas ;

DePinho, Ronald A. .

GENES & DEVELOPMENT, 2006, 20 (22) :3130-3146

[3]

A Colon Cancer-derived Mutant of Kruppel-like Factor 5 (KLF5) Is Resistant to Degradation by Glycogen Synthase Kinase 3β (GSK3β) and the E3 Ubiquitin Ligase F-box and WD Repeat Domain-containing 7α (FBW7α) [J].

Bialkowska, Agnieszka B. ;

Liu, Yang ;

Nandan, Mandayam O. ;

Yang, Vincent W. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (09) :5997-6005

[4]

Organoid Models of Human and Mouse Ductal Pancreatic Cancer [J].

Boj, Sylvia F. ;

Hwang, Chang-Il ;

Baker, Lindsey A. ;

Chio, Iok In Christine ;

Engle, Dannielle D. ;

Corbo, Vincenzo ;

Jager, Myrthe ;

Ponz-Sarvise, Mariano ;

Tiriac, Herve ;

Spector, Mona S. ;

Gracanin, Ana ;

Oni, Tobiloba ;

Yu, Kenneth H. ;

van Boxtel, Ruben ;

Huch, Meritxell ;

Rivera, Keith D. ;

Wilson, John P. ;

Feigin, Michael E. ;

Oehlund, Daniel ;

Handly-Santana, Abram ;

Ardito-Abraham, Christine M. ;

Ludwig, Michael ;

Elyada, Ela ;

Alagesan, Brinda ;

Biffi, Giulia ;

Yordanov, Georgi N. ;

Delcuze, Bethany ;

Creighton, Brianna ;

Wright, Kevin ;

Park, Youngkyu ;

Morsink, Folkert H. M. ;

Molenaar, I. Quintus ;

Rinkes, Inne H. Borel ;

Cuppen, Edwin ;

Hao, Yuan ;

Jin, Ying ;

Nijman, Isaac J. ;

Iacobuzio-Donahue, Christine ;

Leach, Steven D. ;

Pappin, Darryl J. ;

Hammell, Molly ;

Klimstra, David S. ;

Basturk, Olca ;

Hruban, Ralph H. ;

Offerhaus, George Johan ;

Vries, Robert G. J. ;

Clevers, Hans ;

Tuveson, David A. .

CELL, 2015, 160 (1-2) :324-338

[5]

A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells [J].

Burk, Ulrike ;

Schubert, Joerg ;

Wellner, Ulrich ;

Schmalhofer, Otto ;

Vincan, Elizabeth ;

Spaderna, Simone ;

Brabletz, Thomas .

EMBO REPORTS, 2008, 9 (06) :582-589

[6]

Colorectal cancer risk in hamartomatous polyposis syndromes [J].

Campos, Fabio Guilherme ;

Figueiredo, Marleny Novaes ;

Real Martinez, Carlos Augusto .

WORLD JOURNAL OF GASTROINTESTINAL SURGERY, 2015, 7 (03) :25-32

[7]

Suppression of transforming growth factor-β-induced apoptosis through a phosphatidylinositol 3-kinase Akt-dependent pathway [J].

Chen, RH ;

Su, YH ;

Chuang, RLC ;

Chang, TY .

ONCOGENE, 1998, 17 (15) :1959-1968

[8]

Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development [J].

Chia, Na-Yu ;

Deng, Niantao ;

Das, Kakoli ;

Huang, Dachuan ;

Hu, Longyu ;

Zhu, Yansong ;

Lim, Kiat Hon ;

Lee, Ming-Hui ;

Wu, Jeanie ;

Sam, Xin Xiu ;

Tan, Gek San ;

Wan, Wei Keat ;

Yu, Willie ;

Gan, Anna ;

Tan, Angie Lay Keng ;

Tay, Su-Ting ;

Soo, Khee Chee ;

Wong, Wai Keong ;

Dominguez, Lourdes Trinidad M. ;

Ng, Huck-Hui ;

Rozen, Steve ;

Goh, Liang-Kee ;

Teh, Bin-Tean ;

Tan, Patrick .

GUT, 2015, 64 (05) :707-719

[9]

Snail controls differentiation of hepatocytes by repressing HNF4α expression [J].

Cicchini, Carla ;

Filippini, Daniela ;

Coen, Sabrina ;

Marchetti, Alessandra ;

Cavallari, Claudio ;

Laudadio, Ilaria ;

Spagnoli, Francesca M. ;

Alonzi, Tonino ;

Tripodi, Marco .

JOURNAL OF CELLULAR PHYSIOLOGY, 2006, 209 (01) :230-238

[10]

DaCosta BS, 2004, MOL PHARM, V65, P744, DOI DOI 10.1124/M0L.65.3.744

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