BrafV600E cooperates with Pten loss to induce metastatic melanoma

David Dankort, David P. Curley, Robert A. Cartlidge, Betsy Nelson, Anthony Karnezis, William E. Damsky, Mingjian J. You, Ronald A. DePinho, Martin McMahon, Marcus Bosenberg

Research output: Contribution to journalArticle

675 Scopus citations

Abstract

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 BrafV600E. Upon induction of BrafV600E expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BrafV600E 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.

Original languageEnglish (US)
Pages (from-to)544-552
Number of pages9
JournalNature Genetics
Volume41
Issue number5
DOIs
StatePublished - May 1 2009
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Genetics

Cite this

Dankort, D., Curley, D. P., Cartlidge, R. A., Nelson, B., Karnezis, A., Damsky, W. E., You, M. J., DePinho, R. A., McMahon, M., & Bosenberg, M. (2009). BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nature Genetics, 41(5), 544-552. https://doi.org/10.1038/ng.356