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

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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.

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

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Adenocarcinoma
Cytokines
Neoplasms
1-Phosphatidylinositol 4-Kinase
Mutation
Tumor Microenvironment
Gene Deletion
Disease Progression
Molecular Biology
Genome

ASJC Scopus subject areas

  • Oncology

Cite this

Ying, H., Elpek, K. G., Vinjamoori, A., Zimmerman, S. M., Chu, G. C., Yan, H., ... 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

PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network. / Ying, Haoqiang; Elpek, Kutlu G.; Vinjamoori, Anant; Zimmerman, Stephanie M.; Chu, Gerald C.; Yan, Haiyan; Fletcher-Sananikone, Eliot; Zhang, Hailei; Liu, Yingchun; Wang, Wei; Ren, Xiaojia; Zheng, Hongwu; Kimmelman, Alec C.; Paik, Ji hye; Lim, Carol; Perry, Samuel R.; Jiang, Shan; Malinn, Brian; Protopopov, Alexei; Colla, Simona; Xiao, Yonghong; Hezel, Aram F.; Bardeesy, Nabeel; Turley, Shannon J.; Alan Wang, Y.; Chin, Lynda; Thayer, Sarah P.; DePinho, Ronald A.

In: Cancer Discovery, Vol. 1, No. 2, 23.05.2011, p. 158-169.

Research output: Contribution to journalArticle

Ying, H, Elpek, KG, Vinjamoori, A, Zimmerman, SM, Chu, GC, Yan, H, Fletcher-Sananikone, E, Zhang, H, Liu, Y, Wang, W, Ren, X, Zheng, H, Kimmelman, AC, Paik, JH, Lim, C, Perry, SR, Jiang, S, Malinn, B, Protopopov, A, Colla, S, Xiao, Y, Hezel, AF, Bardeesy, N, Turley, SJ, Alan Wang, Y, Chin, L, Thayer, SP & DePinho, RA 2011, 'PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network', Cancer Discovery, vol. 1, no. 2, pp. 158-169. https://doi.org/10.1158/2159-8290.CD-11-0031
Ying, Haoqiang ; Elpek, Kutlu G. ; Vinjamoori, Anant ; Zimmerman, Stephanie M. ; Chu, Gerald C. ; Yan, Haiyan ; Fletcher-Sananikone, Eliot ; Zhang, Hailei ; Liu, Yingchun ; Wang, Wei ; Ren, Xiaojia ; Zheng, Hongwu ; Kimmelman, Alec C. ; Paik, Ji hye ; Lim, Carol ; Perry, Samuel R. ; Jiang, Shan ; Malinn, Brian ; Protopopov, Alexei ; Colla, Simona ; Xiao, Yonghong ; Hezel, Aram F. ; Bardeesy, Nabeel ; Turley, Shannon J. ; Alan Wang, Y. ; Chin, Lynda ; Thayer, Sarah P. ; DePinho, Ronald A. / PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network. In: Cancer Discovery. 2011 ; Vol. 1, No. 2. pp. 158-169.
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AU - Elpek, Kutlu G.

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AU - Zimmerman, Stephanie M.

AU - Chu, Gerald C.

AU - Yan, Haiyan

AU - Fletcher-Sananikone, Eliot

AU - Zhang, Hailei

AU - Liu, Yingchun

AU - Wang, Wei

AU - Ren, Xiaojia

AU - Zheng, Hongwu

AU - Kimmelman, Alec C.

AU - Paik, Ji hye

AU - Lim, Carol

AU - Perry, Samuel R.

AU - Jiang, Shan

AU - Malinn, Brian

AU - Protopopov, Alexei

AU - Colla, Simona

AU - Xiao, Yonghong

AU - Hezel, Aram F.

AU - Bardeesy, Nabeel

AU - Turley, Shannon J.

AU - Alan Wang, Y.

AU - Chin, Lynda

AU - Thayer, Sarah P.

AU - DePinho, Ronald A.

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