ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism
Yanan Yang, … , Chad J. Creighton, Jonathan M. Kurie
Yanan Yang, … , Chad J. Creighton, Jonathan M. Kurie
Published April 24, 2014
Citation Information: J Clin Invest. 2014;124(6):2696-2708. https://doi.org/10.1172/JCI72171.
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ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism

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.

Authors

Yanan 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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Figure 1

Mesenchymal lung adenocarcinoma cells are sensitive to PX-866.

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Mesenchymal lung adenocarcinoma cells are sensitive to PX-866. (A) Survi...
(A) Survival analysis of lung cancer patients comparing differences in risk between tumors according to degree of manifestation of a PI3K/mTOR inhibitor–regulated transcriptional signature. Kaplan-Meier plot compares the top, bottom, and middle thirds of the T-score values. (B) H&E staining of metastatic tumors (arrows) in KP mice. Scale bars: 200 μm. (C) Numbers (n) of visible lung tumors (scatter plot) and mice with (w/) or without (w/o) histologically documented metastases (Met) (bar graph). Metastasis incidence P value (Fisher’s exact test). (D) Invasion assays. In a single experiment, invasive KP cells were quantified after a 24-hour incubation with PX-866 or vehicle. Mean ± SD from triplicate samples. (E) Scatter plots of primary tumor volume and numbers of visible lung metastases in a single experiment in which syngeneic mice were injected with 344SQ cells (5 mice per cohort) or 531LN2 cells (9 mice per cohort) and then treated with PX-866 or vehicle. Mean ± SD was calculated for each cohort. (F and G) Invasion assays. Invasive KP cells (F) and H1299 cells (G) were quantified in the presence or absence of PX-866. H1299 cells were treated with (+) or without (–) doxycycline (Dox) (1 μg/ml) to induce expression of the miR-200b/a/429 construct. Mean ± SD from triplicate samples. vec, vector.