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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 Colla, Yonghong Xiao, Aram F. Hezel, Nabeel Bardeesy, Shannon J. Turley, Y. Alan Wang, Lynda Chin, Sarah P. Thayer and Ronald A. DePinho
Haoqiang Ying
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Kutlu G. Elpek
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Anant Vinjamoori
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Stephanie M. Zimmerman
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Gerald C. Chu
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Haiyan Yan
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Eliot Fletcher-Sananikone
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Hailei Zhang
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Yingchun Liu
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Wei Wang
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Xiaojia Ren
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Hongwu Zheng
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Shan Jiang
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Brian Malinn
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Simona Colla
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Yonghong Xiao
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Aram F. Hezel
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DOI: 10.1158/2159-8290.CD-11-0031 Published July 2011
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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. Cancer Discovery; 1(2); 158–69. ©2011 AACR.

Read the Commentary on this article by Chiao and Ling, p. 103

This article is highlighted in the In This Issue feature, p. 91

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://www.cancerdiscovery.aacrjournals.org).

  • Received February 21, 2011.
  • Revision received May 6, 2011.
  • Accepted May 10, 2011.
  • ©2011 American Association for Cancer Research.
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Cancer Discovery: 1 (2)
July 2011
Volume 1, Issue 2
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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 Colla, Yonghong Xiao, Aram F. Hezel, Nabeel Bardeesy, Shannon J. Turley, Y. Alan Wang, Lynda Chin, Sarah P. Thayer and Ronald A. DePinho
Cancer Discov July 1 2011 (1) (2) 158-169; DOI: 10.1158/2159-8290.CD-11-0031

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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 Colla, Yonghong Xiao, Aram F. Hezel, Nabeel Bardeesy, Shannon J. Turley, Y. Alan Wang, Lynda Chin, Sarah P. Thayer and Ronald A. DePinho
Cancer Discov July 1 2011 (1) (2) 158-169; DOI: 10.1158/2159-8290.CD-11-0031
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