BrafV600E cooperates with Pten loss to induce metastatic melanoma

Abstract

Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. Hence, 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. Importantly, combined treatment with Rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide an excellent system to study melanoma’s cardinal feature of metastasis and for pre-clinical evaluation of agents designed to prevent or treat metastatic disease.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…2). This synergy was most powerfully corroborated in mouse transgenic models in which pairwise activation and inacti vation of NRAS and CDKN2A, BRAF and PTEN, or BRAF and CDKN2A, respectively, gave rise to melanoma with high fidelity 14,15 . Characterization of tumours from large cohorts of patients with advanced-stage melanoma at the whole-genome level has provided greater granularity regarding the overall prevalence of these genetic alterations, as well as their overlap 5,9,16 (FIG.…”

Repression of cancer cell senescence by PKCι

“…In the first model, PKCi could be mediating downstream anti-senescent activity of the PI-3-kinase pathway, which prevents oncogene-induced senescence by a second oncogenic pathway. This model is suggested by data from mouse models of melanoma, where PI-3-kinase pathway signaling appears to prevent oncogene-induced senescence driven by mutant BRAF (Dankort et al, 2009). In an alternate model, PKCi might attenuate oncogene-induced senescence driven by the PI-3-kinase pathway itself.…”

“…In cultured mouse embryonic fibroblasts, the PI-3-kinase inhibitors LY294002 and wortmannin induce senescence (Collado et al, 2000). In mouse models of melanoma, whereas BRAF activation in melanocytes mimics the generation of senescent cells described in human naevi, BRAF activation in mice deleted for PTEN leads to the formation of malignant tumors (Dankort et al, 2009). In contrast to these studies that indicate a role for the PI-3-kinase pathway in suppressing oncogene-induced senescence, other studies have indicated a role for the PI-3-kinase pathway in driving oncogene-induced senescence.…”

Palmitoylation-dependent activation of MC1R prevents melanomagenesis

“…Tyr-Cre-BRAF CA mice (B6.Cg- Braf tm1Mmcm Tg(Tyr-cre/ERT2)13Bos/BosJ) 27 were next crossed to the MC1R e/e , MC1R +/+ , MC1R R151C and MC1R C315S mice and BRAF V600E expression induced by tamoxifen administration. After UVB irradiation each week for four weeks (Extended Data Fig.…”