TY - JOUR
T1 - YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma
AU - Tu, Bo
AU - Yao, Jun
AU - Ferri-Borgogno, Sammy
AU - Zhao, Jun
AU - Chen, Shujuan
AU - Wang, Qiuyun
AU - Yan, Liang
AU - Zhou, Xin
AU - Zhu, Cihui
AU - Bang, Seungmin
AU - Chang, Qing
AU - Bristow, Christopher A.
AU - Kang, Yaan
AU - Zheng, Hongwu
AU - Wang, Huamin
AU - Fleming, Jason B.
AU - Kim, Michael
AU - Heffernan, Timothy P.
AU - Draetta, Giulio F.
AU - Pan, Duojia
AU - Maitra, Anirban
AU - Yao, Wantong
AU - Gupta, Sonal
AU - Ying, Haoqiang
N1 - Funding Information:
We thank the laboratory of Ben Stanger for sharing mouse PDAC cell line PD3077. We would like to thank the Institute for Applied Cancer Science, the Flow Cytometry and Cellular Imaging Core at The University of Texas MD Anderson Cancer Center, and the Veterinary Medicine Department at MD Anderson (Cancer Center Support Grant CA016672). We thank Ronald DePinho, Alan Wang, Mien-Chie Hung, Guocan Wang, Baoli Hu, Xin Zhou, and Jihye Paik for helpful discussions and critical reviews. The research was supported by the Pancreatic Cancer Action Network-American Association for Cancer Research Career Development Award and National Cancer Institute (NCI) grant R01CA214793 to HY, the Pancreatic Cancer Action Network-American Association for Cancer Research Pathway to Leadership Award to WY, the Seed Grant from Hirshberg Foundation for Pancreatic Cancer Research to HY and WY, and NCI P01 grant P01CA117969 to HW, JBF, MK, GFD, AM, and HY.
Publisher Copyright:
© 2019 American Society for Clinical Investigation. All rights reserved.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and their correlation with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, the squamous subtype is relatively independent of oncogenic KRAS signaling and typically displays much more aggressive clinical behavior versus the progenitor subtype. Here, we identified that yes-Associated protein 1 (YAP1) activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC cells. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and YAP1 activity in human PDAC and demonstrated that WNT5A overexpression led to YAP1 activation and recapitulated a YAP1-dependent but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A in driving PDAC malignancy through activation of the YAP pathway.
AB - Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and their correlation with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, the squamous subtype is relatively independent of oncogenic KRAS signaling and typically displays much more aggressive clinical behavior versus the progenitor subtype. Here, we identified that yes-Associated protein 1 (YAP1) activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC cells. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and YAP1 activity in human PDAC and demonstrated that WNT5A overexpression led to YAP1 activation and recapitulated a YAP1-dependent but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A in driving PDAC malignancy through activation of the YAP pathway.
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U2 - 10.1172/jci.insight.130811
DO - 10.1172/jci.insight.130811
M3 - Article
C2 - 31557131
AN - SCOPUS:85076605145
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 21
M1 - e130811
ER -