Discovering novel metabolic vulnerabilities in melanoma metastasis

• Applicant: Professor Dr. Alpaslan Tasdogan
• Subject Area: Dermatology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467788900

Malignant melanoma is the most aggressive form of skin cancer with a high rate of metastasis.Metastasis is responsible for more than 90% of cancer patient mortality yet there are no therapies that specifically target metastatic disease. Cancer metastasis is a highly inefficient process. However, rare disseminated metastatic cells are able to adapt to local microenvironments and survive to form metastases at distant organs. One factor that limits metastasis is oxidative stress that cancer cells experience during metastasis. Cancer cells have to undergo important metabolic changes and adaptations that enable them to withstand metabolic stress and transition through the hostile metastatic process. In order to improve therapeutic outcomes, it is of utmost importance to better understand the underlying molecular and metabolic mechanisms of metastasizing cancer cells. My proposal will use a clinically relevant model of melanoma metastasis to dissect metabolic adaptations that occur during metastasis to identify novel metabolic vulnerabilities and targets for improved cancer treatments. The proposed research program includes following aims: I. To determine the relative contribution of the polyamine pathway during melanoma metastasis by genetically testing the functional necessity of the polyamine pathway for metastasizing melanoma cells in vivo. We will also assess the molecular mechanism using metabolomics and gene expression analysis by which inhibition of polyamine synthesis affects melanoma metastasis in vivo. II. To better understand the metabolic changes required for metastasizing cells using in situ analysis of metastases in distant organs. Metastatic cells undergo important metabolic changes that enable them to survive dissemination through the blood. Yet, metastasis to specific organs, or “metastatic organotropism”, is a non-random process. The metabolic pathway regulating this process is not well understood, but in situ analyses will help to reveal novel metabolic vulnerabilities of metastatic melanoma cells. III. To assess the metabolic heterogeneity of metastatic murine melanoma cells and immune cells in primary tumors and distant organs in situ in an immunocompetent melanoma mouse model. Immune cells play an important role in antitumor immunity. However, the metabolic crosstalk between cancer cells and immune cells is not well characterized. In this aim, we will assess immune cell metabolism in the tumor microenvironment of distant organs to identify relevant metabolic pathways changes during cancer metastasis. Our overarching goal is to uncover new pathways that regulate metastasis and potentially novel metabolic vulnerabilities in metastasizing melanoma cells. Based on our findings, future clinical trials could focus on testing anti-metastatic metabolic agents with the potential to improve treatment outcomes in melanoma, and in other cancers.

• DFG Programme: Independent Junior Research Groups