BrafV600E cooperates with Pten loss to induce metastatic melanoma
| Autor: | Marcus Bosenberg, Anthony N. Karnezis, William Damsky, Robert A. Cartlidge, Betsy Nelson, David P. Curley, Mingjian James You, Martin McMahon, David Dankort, Ronald A. DePinho |
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| Rok vydání: | 2009 |
| Předmět: | |
| Zdroj: | Nature Genetics. 41:544-552 |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/ng.356 |
| Popis: | Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional melanocyte-specific expression of BRaf(V600E). Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or treat metastatic disease. |
| Databáze: | OpenAIRE |
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