Article abstract
Nature Genetics 41, 544 - 552 (2009)
Published online: 12 March 2009 | doi:10.1038/ng.356
BrafV600E cooperates with Pten loss to induce metastatic melanoma
David Dankort1,5,6, David P Curley2,6, Robert A Cartlidge1, Betsy Nelson2, Anthony N Karnezis3, William E Damsky Jr2, Mingjian J You4,5, Ronald A DePinho4, Martin McMahon1 & Marcus Bosenberg2,5
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.
- Cancer Research Institute & Department of Cell and Molecular Pharmacology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
- Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA.
- Cancer Research Institute & Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
- Belfer Institute for Applied Cancer Science, Departments of Medical Oncology, Medicine & Genetics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
- Present addresses: Department of Biology, McGill University, Montreal, Canada, H3A 1B1 (D.D.); Department of Hematopathlogy, Division of Pathology and Laboratory Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA (M.J.Y.); Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA (M.B.).
- These authors contributed equally to this work.
Correspondence to: Martin McMahon1 e-mail: mcmahon@cc.ucsf.edu
Correspondence to: Marcus Bosenberg2,5 e-mail: marcus.bosenberg@yale.edu
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