ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism.
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.
Yanan
Y
Yang
Young-Ho
YH
Ahn
Yulong
Y
Chen
Xiaochao
X
Tan
Lixia
L
Guo
Don L
DL
Gibbons
Christin
C
Ungewiss
David H
DH
Peng
Xin
X
Liu
Steven H
SH
Lin
Nishan
N
Thilaganathan
Ignacio I
II
Wistuba
Jaime
J
Rodriguez-Canales
Georgia
G
McLendon
Chad J
CJ
Creighton
Jonathan M
JM
Kurie
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006067:Gonanes / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary*; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D006067:Gonanes; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; C496788:PX-866; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; C541485:EGFR protein, mouse; C524056:Erbb2 protein, mouse; C495971:Hras protein, mouse