PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network

Haoqiang Ying, Kutlu G. Elpek, Anant Vinjamoori, Stephanie M. Zimmerman, Gerald C. Chu, Haiyan Yan, Eliot Fletcher-Sananikone, Hailei Zhang, Yingchun Liu, Wei Wang, Xiaojia Ren, Hongwu Zheng, Alec C. Kimmelman, Ji hye Paik, Carol Lim, Samuel R. Perry, Shan Jiang, Brian Malinn, Alexei Protopopov, Simona CollaYonghong Xiao, Aram F. Hezel, Nabeel Bardeesy, Shannon J. Turley, Y. Alan Wang, Lynda Chin, Sarah P. Thayer, Ronald A. DePinho

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

Initiation of pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS mutation, and disease progression is associated with frequent loss of tumor suppressors. In this study, human PDAC genome analyses revealed frequent deletion of the PTEN gene as well as loss of expression in primary tumor specimens. A potential role for PTEN as a haploinsufficient tumor suppressor is further supported by mouse genetic studies. The mouse PDAC driven by oncogenic Kras mutation and Pten deficiency also sustains spontaneous extinction of Ink4a expression and shows prometastatic capacity. Unbiased transcriptomic analyses established that combined oncogenic Kras and Pten loss promotes marked NF-κB activation and its cytokine network, with accompanying robust stromal activation and immune cell infiltration with known tumor-promoting properties. Thus, PTEN/phosphoinositide 3-kinase (PI3K) pathway alteration is a common event in PDAC development and functions in part to strongly activate the NF-κB network, which may serve to shape the PDAC tumor microenvironment. Significance: Detailed molecular genetics studies established that PTEN operates as a haploinsufficient tumor suppressor to promote metastatic PDAC development. The strong activation of the NF-κB-cytokine program in Pten-deficient tumors provides additional avenues for targeted therapies in tumors with altered PI3K regulation.

Original languageEnglish (US)
Pages (from-to)158-169
Number of pages12
JournalCancer Discovery
Volume1
Issue number2
DOIs
StatePublished - May 23 2011

ASJC Scopus subject areas

  • Oncology

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    Ying, H., Elpek, K. G., Vinjamoori, A., Zimmerman, S. M., Chu, G. C., Yan, H., Fletcher-Sananikone, E., Zhang, H., Liu, Y., Wang, W., Ren, X., Zheng, H., Kimmelman, A. C., Paik, J. H., Lim, C., Perry, S. R., Jiang, S., Malinn, B., Protopopov, A., ... DePinho, R. A. (2011). PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network. Cancer Discovery, 1(2), 158-169. https://doi.org/10.1158/2159-8290.CD-11-0031