BrafV600E cooperates with Pten loss to induce metastatic melanoma

摘要: Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model melanoma, we generated mice with conditional melanocyte-specific expression BRaf(V600E). Upon induction BRaf(V600E) expression, developed benign melanocytic hyperplasias that failed to progress melanoma over 15-20 months. By contrast, combined Pten tumor suppressor gene silencing elicited development 100% penetrance, short latency metastases observed lymph nodes lungs. Melanoma was prevented by inhibitors mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation drug administration, indicating presence long-lived melanoma-initiating cells this system. Notably, treatment rapamycin PD325901 led shrinkage established melanomas. These mice, engineered profile provide system study melanoma's cardinal feature metastasis for preclinical evaluation agents designed prevent treat metastatic disease.