Journal Article

Inactivation of Capicua drives cancer metastasis

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

2017

Overview

Trever Bivona and colleagues use an in vivo lung cancer metastasis model to show that the transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. CIC inactivation leads to upregulation of ETV4 and MMP24, which is necessary and sufficient for metastasis. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1612/1350 / 631/67/322 / Adenovirus E1A Proteins - genetics / Adenovirus E1A Proteins - metabolism / Agriculture / Animal Genetics and Genomics / Animals / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - metabolism / Carcinoma, Non-Small-Cell Lung - secondary / Female / Gene Expression Profiling / Gene Function / Human Genetics / Humans / Inactivation / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Matrix Metalloproteinases, Membrane-Associated - genetics / Matrix Metalloproteinases, Membrane-Associated - metabolism / Metastasis / Mice / Mice, SCID / Mutation / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Repressor Proteins - antagonists & inhibitors / Repressor Proteins - genetics / Repressor Proteins - metabolism / Rodents / Studies / Tumor Cells, Cultured / Tumors