Braf(V600E) Cooperates With Pten Loss to Induce Metastatic Melanoma

Nat Genet. 2009 May;41(5):544-52. doi: 10.1038/ng.356. Epub 2009 Mar 12.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Mechanistic Target of Rapamycin Complex 1
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mice
  • Mice, Transgenic
  • Multiprotein Complexes
  • Neoplasm Metastasis
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism
  • Proteins
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / metabolism
  • TOR Serine-Threonine Kinases
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Multiprotein Complexes
  • Proteins
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins B-raf
  • PTEN Phosphohydrolase