Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.
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.
Dankort
David
D
Cancer Research Institute & Department of Cell and Molecular Pharmacology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA.
Curley
David P
DP
Cartlidge
Robert A
RA
Nelson
Betsy
B
Karnezis
Anthony N
AN
Damsky
William E
WE
You
Mingjian J
MJ
DePinho
Ronald A
RA
McMahon
Martin
M
Bosenberg
Marcus
M
D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000076222:Mechanistic Target of Rapamycin Complex 1; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011506:Proteins; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase