Impact of endosomal cholesterol trafficking on melanoma metastasis

Patients suffering from metastatic melanoma are confronted with a very poor prognosis. Despite recent success of targeted therapies against the mutated BRAF oncogene, the mean 5-year overall survival rate for stage IV melanoma patients is alarmingly low. Here, we propose that late endosomal cholesterol transport is linked with the potential for melanoma to metastasize, since our preliminary data show that distinct cholesterol transporters are selectively over-expressed in metastatic melanoma cells. Moreover, cholesterol transporter expression negatively correlates with patient survival. Interestingly, addition of exogenous cholesterol to non-metastatic melanoma cells induces S6 as well as PI3K/AKT activity, which dependents on late endosomal cholesterol flux. Thus, our central hypothesis is that blocking late endosomal cholesterol export reduces the ability of melanoma to metastasize. We aim in this project to characterize altered cholesterol homeostasis as part of the metastatic signature in malignant melanoma. We will dissect lipid status, cholesterol transporter expression and cholesterol trafficking in melanoma skin tumors and melanoma lymph node metastasis in mouse models that faithfully reflect human melanoma progression (BRAFV600E PTEN-/- and N-RasQ61K Ink4a-/- mice). In-vitro studies with different mouse and human primary melanoma derived cell lines will assess the mechanisms of the pro-metastatic effect of cholesterol, focusing on the S6, PI3K/AKT and MAPK pathway. In addition, we will analyze markers of proliferation, invasion and metastasis in response to exogenous cholesterol. Inhibitors of intracellular cholesterol trafficking will be tested for their potential to revert these effects and to exert synergistic effects with already established drugs. Finally, selected cholesterol trafficking inhibitors alone or in combination with established drugs will be tested in melanoma xenograft mouse models to suppress tumor progression and metastasis. Overall, our findings will raise knowledge on cholesterol metabolism during melanoma metastasis. Novel therapeutic approaches targeting metabolic changes during melanoma progression might emerge from this project.

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