Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer

被引：255

作者：

Kapoor, Avnish ^{[2
]}

Yao, Wantong ^{[2
,3
]}

Ying, Haoqiang ^{[2
,3
]}

Hua, Sujun ^{[2
]}

Liewen, Alison ^{[2
]}

Wang, Qiuyun ^{[2
]}

Zhong, Yi ^{[4
]}

Wu, Chang-Jiun ^{[2
]}

Sadanandam, Anguraj ^{[7
,8
]}

Hu, Baoli ^{[2
]}

Chang, Qing ^{[4
]}

Chu, Gerald C. ^{[9
]}

Al-Khalil, Ramsey ^{[2
]}

Jiang, Shan ^{[2
]}

Xia, Hongai ^{[2
]}

Fletcher-Sananikone, Eliot ^{[2
]}

Lim, Carol ^{[2
]}

Horwitz, Gillian I. ^{[2
]}

Viale, Andrea ^{[2
,3
]}

Pettazzoni, Piergiorgio ^{[2
,3
]}

Sanchez, Nora ^{[2
,3
]}

Wang, Huamin ^{[5
]}

Protopopov, Alexei ^{[4
]}

Zhang, Jianhua ^{[4
]}

Heffernan, Timothy ^{[4
]}

Johnson, Randy L. ^{[6
]}

Chin, Lynda ^{[2
,4
]}

Wang, Y. Alan ^{[2
]}

Draetta, Giulio ^{[2
,3
,4
]}

DePinho, Ronald A. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA

[7] Inst Canc Res, Sutton SM2 5NG, Surrey, England

[8] Swiss Fed Inst Technol Lausanne EPFL, Swiss Inst Expt Canc Res ISREC, Stn 19, CH-1015 Lausanne, Switzerland

[9] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

来源：

CELL | 2014年 / 158卷 / 01期

基金：

美国国家卫生研究院;

关键词：

HIPPO PATHWAY; GROWTH; ADENOCARCINOMA; PROLIFERATION; INACTIVATION; INHIBITION; RESISTANCE; INDUCTION; TARGET;

D O I：

10.1016/j.cell.2014.06.003

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras(G12D) driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.

引用

页码：185 / 197

页数：13

共 45 条

[1]

Adams PD, 1996, CURR TOP MICROBIOL, V208, P79

[2] Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse [J].

Bardeesy, N ;

Aguirre, AJ ;

Chu, GC ;

Cheng, KH ;

Lopez, LV ;

Hezel, AF ;

Feng, B ;

Brennan, C ;

Weissleder, R ;

Mahmood, U ;

Hanahan, D ;

Redston, MS ;

Chin, L ;

DePinho, RA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (15) :5947-5952

[3] Understanding resistance to targeted cancer drugs through loss of function genetic screens [J].

Berns, Katrien ;

Bernards, Rene .

DRUG RESISTANCE UPDATES, 2012, 15 (5-6) :268-275

[4] Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes [J].

Biankin, Andrew V. ;

Waddell, Nicola ;

Kassahn, Karin S. ;

Gingras, Marie-Claude ;

Muthuswamy, Lakshmi B. ;

Johns, Amber L. ;

Miller, David K. ;

Wilson, Peter J. ;

Patch, Ann-Marie ;

Wu, Jianmin ;

Chang, David K. ;

Cowley, Mark J. ;

Gardiner, Brooke B. ;

Song, Sarah ;

Harliwong, Ivon ;

Idrisoglu, Senel ;

Nourse, Craig ;

Nourbakhsh, Ehsan ;

Manning, Suzanne ;

Wani, Shivangi ;

Gongora, Milena ;

Pajic, Marina ;

Scarlett, Christopher J. ;

Gill, Anthony J. ;

Pinho, Andreia V. ;

Rooman, Ilse ;

Anderson, Matthew ;

Holmes, Oliver ;

Leonard, Conrad ;

Taylor, Darrin ;

Wood, Scott ;

Xu, Qinying ;

Nones, Katia ;

Fink, J. Lynn ;

Christ, Angelika ;

Bruxner, Tim ;

Cloonan, Nicole ;

Kolle, Gabriel ;

Newell, Felicity ;

Pinese, Mark ;

Mead, R. Scott ;

Humphris, Jeremy L. ;

Kaplan, Warren ;

Jones, Marc D. ;

Colvin, Emily K. ;

Nagrial, Adnan M. ;

Humphrey, Emily S. ;

Chou, Angela ;

Chin, Venessa T. ;

Chantrill, Lorraine A. .

NATURE, 2012, 491 (7424) :399-405

[5] YAP regulates neural progenitor cell number via the TEA domain transcription factor [J].

Cao, Xinwei ;

Pfaff, Samuel L. ;

Gage, Fred H. .

GENES & DEVELOPMENT, 2008, 22 (23) :3320-3334

[6] A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma [J].

Collisson, Eric A. ;

Trejo, Christy L. ;

Silva, Jillian M. ;

Gu, Shenda ;

Korkola, James E. ;

Heiser, Laura M. ;

Charles, Roch-Philippe ;

Rabinovich, Brian A. ;

Hann, Byron ;

Dankort, David ;

Spellman, Paul T. ;

Phillips, Wayne A. ;

Gray, Joe W. ;

McMahon, Martin .

CANCER DISCOVERY, 2012, 2 (08) :685-693

[7] Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy [J].

Collisson, Eric A. ;

Sadanandam, Anguraj ;

Olson, Peter ;

Gibb, William J. ;

Truitt, Morgan ;

Gu, Shenda ;

Cooc, Janine ;

Weinkle, Jennifer ;

Kim, Grace E. ;

Jakkula, Lakshmi ;

Feiler, Heidi S. ;

Ko, Andrew H. ;

Olshen, Adam B. ;

Danenberg, Kathleen L. ;

Tempero, Margaret A. ;

Spellman, Paul T. ;

Hanahan, Douglas ;

Gray, Joe W. .

NATURE MEDICINE, 2011, 17 (04) :500-U140

[8] Selective Requirement of PI3K/PDK1 Signaling for Kras Oncogene-Driven Pancreatic Cell Plasticity and Cancer [J].

Eser, Stefan ;

Reiff, Nina ;

Messer, Marlena ;

Seidler, Barbara ;

Gottschalk, Kathleen ;

Dobler, Melanie ;

Hieber, Maren ;

Arbeiter, Andreas ;

Klein, Sabine ;

Kong, Bo ;

Michalski, Christoph W. ;

Schlitter, Anna Melissa ;

Esposito, Irene ;

Kind, Alexander J. ;

Rad, Lena ;

Schnieke, Angelika E. ;

Baccarini, Manuela ;

Alessi, Dario R. ;

Rad, Roland ;

Schmid, Roland M. ;

Schneider, Guenter ;

Saur, Dieter .

CANCER CELL, 2013, 23 (03) :406-420

[9] YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation [J].

Fernandez-L, Africa ;

Northcott, Paul A. ;

Dalton, James ;

Fraga, Charles ;

Ellison, David ;

Angers, Stephane ;

Taylor, Michael D. ;

Kenney, Anna Marie .

GENES & DEVELOPMENT, 2009, 23 (23) :2729-2741

[10] BASIC AND TRANSLATIONAL-PANCREAS [J].

Gao, Tao ;

Zhou, Dawang ;

Yang, Chenghua ;

Singh, Tarjinder ;

Penzo-Mendez, Alfredo ;

Maddipati, Ravikanth ;

Tzatsos, Alexandros ;

Bardeesy, Nabeel ;

Avruch, Joseph ;

Stanger, Ben Z. .

GASTROENTEROLOGY, 2013, 144 (07) :1543-U380

← 1 2 3 4 5 →