ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism

Yanan D Yang, Young Ho Ahn, Yulong Chen, Xiaochao Tan, Lixia Guo, Don L. Gibbons, Christin Ungewiss, David H. Peng, Xin Liu, Steven H. Lin, Nishan Thilaganathan, Ignacio I. Wistuba, Jaime Rodriguez-Canales, Georgia McLendon, Chad J. Creighton, Jonathan M. Kurie

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Abstract

Epithelial tumor cells that have undergone epithelial-to-mesenchymal transition (EMT) are typically prone to metastasis and drug resistance and contribute to a poor clinical outcome. The transcription factor ZEB1 is a known driver of EMT, and mediators of ZEB1 represent potential therapeutic targets for metastasis suppression. Here, we have shown that phosphatidylinositol 3-kinase-targeted (PI3K-targeted) therapy suppresses metastasis in a mouse model of Kras/Tp53-mutant lung adenocarcinoma that develops metastatic disease due to high expression of ZEB1. In lung adenocarcinoma cells from Kras/Tp53-mutant animals and human lung cancer cell lines, ZEB1 activated PI3K by derepressing miR-200 targets, including amphiregulin (AREG), betacellulin (BTC), and the transcription factor GATA6, which stimulated an EGFR/ERBB2 autocrine loop. Additionally, ZEB1-dependent derepression of the miR-200 and miR-183 target friend of GATA 2 (FOG2) enhanced GATA3-induced expression of the p110α catalytic subunit of PI3K. Knockdown of FOG2, p110α, and RHEB ameliorated invasive and metastatic propensities of tumor cells. Surprisingly, FOG2 was not required for mesenchymal differentiation, suggesting that mesenchymal differentiation and invasion are distinct and separable processes. Together, these results indicate that ZEB1 sensitizes lung adenocarcinoma cells to metastasis suppression by PI3K-targeted therapy and suggest that treatments to selectively modify the metastatic behavior of mesenchymal tumor cells are feasible and may be of clinical value.

Original languageEnglish (US)
Pages (from-to)2696-2708
Number of pages13
JournalJournal of Clinical Investigation
Volume124
Issue number6
DOIs
StatePublished - Jun 2 2014

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Phosphatidylinositol 3-Kinases
Phosphatidylinositol 3-Kinase
Neoplasm Metastasis
Epithelial-Mesenchymal Transition
GATA6 Transcription Factor
Neoplasms
Therapeutics
Drug Resistance
Lung Neoplasms
Catalytic Domain
Transcription Factors
Epithelial Cells
Cell Line
Adenocarcinoma of lung

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yang, Y. D., Ahn, Y. H., Chen, Y., Tan, X., Guo, L., Gibbons, D. L., ... Kurie, J. M. (2014). ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism. Journal of Clinical Investigation, 124(6), 2696-2708. https://doi.org/10.1172/JCI72171

ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism. / Yang, Yanan D; Ahn, Young Ho; Chen, Yulong; Tan, Xiaochao; Guo, Lixia; Gibbons, Don L.; Ungewiss, Christin; Peng, David H.; Liu, Xin; Lin, Steven H.; Thilaganathan, Nishan; Wistuba, Ignacio I.; Rodriguez-Canales, Jaime; McLendon, Georgia; Creighton, Chad J.; Kurie, Jonathan M.

In: Journal of Clinical Investigation, Vol. 124, No. 6, 02.06.2014, p. 2696-2708.

Research output: Contribution to journalArticle

Yang, YD, Ahn, YH, Chen, Y, Tan, X, Guo, L, Gibbons, DL, Ungewiss, C, Peng, DH, Liu, X, Lin, SH, Thilaganathan, N, Wistuba, II, Rodriguez-Canales, J, McLendon, G, Creighton, CJ & Kurie, JM 2014, 'ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism', Journal of Clinical Investigation, vol. 124, no. 6, pp. 2696-2708. https://doi.org/10.1172/JCI72171
Yang, Yanan D ; Ahn, Young Ho ; Chen, Yulong ; Tan, Xiaochao ; Guo, Lixia ; Gibbons, Don L. ; Ungewiss, Christin ; Peng, David H. ; Liu, Xin ; Lin, Steven H. ; Thilaganathan, Nishan ; Wistuba, Ignacio I. ; Rodriguez-Canales, Jaime ; McLendon, Georgia ; Creighton, Chad J. ; Kurie, Jonathan M. / ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 6. pp. 2696-2708.
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AU - Ahn, Young Ho

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AU - Gibbons, Don L.

AU - Ungewiss, Christin

AU - Peng, David H.

AU - Liu, Xin

AU - Lin, Steven H.

AU - Thilaganathan, Nishan

AU - Wistuba, Ignacio I.

AU - Rodriguez-Canales, Jaime

AU - McLendon, Georgia

AU - Creighton, Chad J.

AU - Kurie, Jonathan M.

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AB - Epithelial tumor cells that have undergone epithelial-to-mesenchymal transition (EMT) are typically prone to metastasis and drug resistance and contribute to a poor clinical outcome. The transcription factor ZEB1 is a known driver of EMT, and mediators of ZEB1 represent potential therapeutic targets for metastasis suppression. Here, we have shown that phosphatidylinositol 3-kinase-targeted (PI3K-targeted) therapy suppresses metastasis in a mouse model of Kras/Tp53-mutant lung adenocarcinoma that develops metastatic disease due to high expression of ZEB1. In lung adenocarcinoma cells from Kras/Tp53-mutant animals and human lung cancer cell lines, ZEB1 activated PI3K by derepressing miR-200 targets, including amphiregulin (AREG), betacellulin (BTC), and the transcription factor GATA6, which stimulated an EGFR/ERBB2 autocrine loop. Additionally, ZEB1-dependent derepression of the miR-200 and miR-183 target friend of GATA 2 (FOG2) enhanced GATA3-induced expression of the p110α catalytic subunit of PI3K. Knockdown of FOG2, p110α, and RHEB ameliorated invasive and metastatic propensities of tumor cells. Surprisingly, FOG2 was not required for mesenchymal differentiation, suggesting that mesenchymal differentiation and invasion are distinct and separable processes. Together, these results indicate that ZEB1 sensitizes lung adenocarcinoma cells to metastasis suppression by PI3K-targeted therapy and suggest that treatments to selectively modify the metastatic behavior of mesenchymal tumor cells are feasible and may be of clinical value.

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