Project Details
Projekt
Harnessing ferroptosis as a potential therapeutic target against melanoma-associated central nervous system metastases
Applicant
Dr. Ioana Todoran née Stejerean
Subject Area
Cell Biology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 549844417
Ferroptosis is emerging as a promising therapeutic approach for targeting drug-resistant tumors, including melanoma. Melanoma, the deadliest of skin cancers, has a high propensity to develop brain metastases (MBM) which dramatically worsen patient outcomes. Despite recent therapeutic advances, the treatment of MBM is still challenging as therapy resistance and cancer relapses commonly occur. Melanoma distant metastases are particularly reliant on redox regulation for survival and drug resistance. However, how metastatic melanoma cells control their redox homeostasis and thereby ferroptosis to evade systemic therapies is scarcely known. Our preliminary data indicate that MBM cells are more susceptible to ferroptotic cell death than their extracranial counterparts. Moreover, we recently demonstrated that mitochondrial calcium homeostasis determines MBM sensitivity to ferroptosis inducers. To identify MBM-specific regulators of ferroptosis, we performed proteome analyses in a panel of human melanoma cell lines. Our results revealed acyl-CoA synthetase long-chain family member 4 (ACSL4) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1) as upregulated in MBM cells and we postulate that these ferroptosis-associated players control MBM cell susceptibility to ferroptosis. Pharmacological inhibition of ACSL4 and FDFT1 conferred MBM protection from RSL3-induced ferroptosis. Additionally, our preliminary tests indicate that lipid metabolism remodeling via inhibition of both ACSL4 and FDFT1 has an impact on natural killer (NK) cell-mediated melanoma cytotoxicity, unraveling novel potential therapeutic strategies against advanced melanoma. Based on these preliminary findings, the main goals of this project proposal are to characterize the redox profiles of MBM cells, to investigate the importance of ACSL4 and FDFT1 in MBM aggressive behavior, to determine environmental factors that affect their expression and to explore the therapeutic significance of ACSL4 and FDFT1 and ferroptosis-modulating drugs (in combination with targeted- and immunotherapies) in MBM aggressive behavior.
DFG Programme
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