Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.
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Gene Expression Omnibus
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R.A.O. was supported by the A.P. Giannini Foundation and NIHT32CA177555-01. T.G.B. acknowledges support from NIH Director's New Innovator Award DP2 CA174497, NIH/NCI RO1 CA169338, and the Pew-Stewart Foundation Trusts. We thank B. Hann (UCSF Preclinical Therapeutics Core) for helpful discussions. The lentiviral GFP-Luc vector was a kind gift from M. Jensen (Seattle Children's Research Institute, Seattle, Washington, USA).
H.J.H. and A.D.S. are employees of Clovis Oncology. K.G., J.S., V.A.M., and S. Ali are employees of Foundation Medicine. T.G.B. is a consultant to Novartis, Astellas, Array Biopharma, Ariad, Teva, and Astrazeneca, and has received research funding from Ignyta.
Supplementary Figures 1–15 and Supplementary Tables 1 and 5 (PDF 41965 kb)
Top 1,500 differentially expressed genes between H1975 M1 (CIC null) and H1975 M1 with reconstituted CIC expression (XLSX 137 kb)
Top 1,000 differentially expressed genes between H1975 and H1975 M1 cells. Ranked by P value. Fold change and log2 fold change are also provided. (XLSX 117 kb)
Top 1,000 differentially expressed genes between H1975 and H1975 M2 cells. Ranked by P value. Fold change and log2 fold change are also provided. (XLSX 121 kb)
267 putative CIC response genes. (XLSX 82 kb)
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