Inactivation of Capicua drives cancer metastasis

Ross A. Okimoto, Frank Breitenbuecher, Victor R. Olivas, Wei Wu, Beatrice Gini, Matan Hofree, Saurabh Asthana, Gorjan Hrustanovic, Jennifer Flanagan, Asmin Tulpule, Collin M. Blakely, Henry J. Haringsma, Andrew D. Simmons, Kyle Gowen, James Suh, Vincent A. Miller, Siraj Ali, Martin Schuler, Trever G. Bivona*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)87-96
Number of pages10
JournalNature Genetics
Volume49
Issue number1
DOIs
StatePublished - 1 Jan 2017
Externally publishedYes

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

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