Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation
| Autor: | Hua Gao, Ai Ping Lee-Lim, Filippo G. Giancotti, Goutam Chakraborty, Konstantinos J. Mavrakis, Hans-Guido Wendel |
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| Rok vydání: | 2014 |
| Předmět: |
DNA
Complementary Lung Neoplasms Virus Integration Genetic Vectors Biology law.invention Mice Proviruses Transduction Genetic law Cell Line Tumor microRNA Animals Genomic library RNA Neoplasm Neoplasm Metastasis RNA Small Interfering Gene Gene Library Mice Inbred BALB C Multidisciplinary Carcinoma Mammary Neoplasms Experimental Expression Library Tail vein DNA Neoplasm Biological Sciences High-Throughput Screening Assays Neoplasm Proteins Gene Expression Regulation Neoplastic MicroRNAs Retroviridae Cancer research Suppressor Female Neoplasm Transplantation Genes Neoplasm Genetic screen |
| Zdroj: | Proceedings of the National Academy of Sciences. 111:16532-16537 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1403234111 |
| Popis: | We have developed a screening platform for the isolation of genetic entities involved in metastatic reactivation. Retroviral libraries of cDNAs from fully 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. |
| Databáze: | OpenAIRE |
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