YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma

Bo Tu, Jun Yao, Sammy Ferri-Borgogno, Jun Zhao, Shujuan Chen, Qiuyun Wang, Liang Yan, Xin Zhou, Cihui Zhu, Seungmin Bang, Qing Chang, Christopher A. Bristow, Yaan Kang, Hongwu Zheng, Huamin Wang, Jason B. Fleming, Michael Kim, Timothy P. Heffernan, Giulio F. Draetta, Duojia PanAnirban Maitra, Wantong Yao, Sonal Gupta, Haoqiang Ying

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere130811
JournalJCI Insight
Volume4
Issue number21
DOIs
StatePublished - Nov 1 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Tu, B., Yao, J., Ferri-Borgogno, S., Zhao, J., Chen, S., Wang, Q., Yan, L., Zhou, X., Zhu, C., Bang, S., Chang, Q., Bristow, C. A., Kang, Y., Zheng, H., Wang, H., Fleming, J. B., Kim, M., Heffernan, T. P., Draetta, G. F., ... Ying, H. (2019). YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma. JCI Insight, 4(21), [e130811]. https://doi.org/10.1172/jci.insight.130811