Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

Hua Gao, Goutam Chakraborty, Ai Ping Lee-Lim, Konstantinos J. Mavrakis, Hans Guido Wendel, Filippo G. Giancotti

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

We have developed a screening platform for the isolation of genetic entities involved in metastatic reactivation. Retroviral libraries of cDNAs fromfully metastatic breast-cancer cells or pooled microRNAs were transduced into breast-cancer cells that become dormant upon infiltrating the lung. Upon inoculation in the tail vein of mice, the cells that had acquired the ability to undergo reactivation generated metastatic lesions. Integrated retroviral vectors were recovered from these lesions, sequenced, and subjected to a second round of validation. By using this strategy, we isolated canonical genes and microRNAs that mediate metastatic reactivation in the lung. To identify genes that oppose reactivation, we screened an expression library encoding shRNAs, and we identified target genes that encode potential enforcers of dormancy. Our screening strategy enables the identification and rapid biological validation of single genetic entities that are necessary to maintain dormancy or to induce reactivation. This technology should facilitate the elucidation of the molecular underpinnings of these processes.

Original languageEnglish (US)
Pages (from-to)16532-16537
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number46
DOIs
StatePublished - Nov 18 2014

ASJC Scopus subject areas

  • General

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