Abstract 279: Lysosomal cyst(e)ine regulates melanoma de-differentiation and sensitivity to ferroptosis

Abstract

Abstract In response to anti-melanoma treatment, melanoma cells go through a process called de-differentiation that is characterized as loss of cellular features of melanocytes and acquisition of traits of the primitive neural crest stem cells which give rise to melanocytes during embryonic development. While de-differentiation enables melanoma to resist anti-melanoma drugs, it also exposes certain vulnerabilities of melanoma. A recent study showed that de-differentiated melanoma cells, while resistant to standard anti-melanoma therapies, display remarkable sensitivity to a group of chemicals that cause a special type of cell death called ferroptosis. However, the cellular programs and molecular machineries that drive melanoma de-differentiation and make them vulnerable to ferroptosis remain unknown. As the master regulator of melanocyte differentiation, MITF is often lost during de-differentiation and this loss has been correlated with sensitivity to ferroptosis. Through proteomic profiling of melanoma cells with different MITF status, we found that MITF-mediated lysosomal biogenesis is a key difference between differentiated melanoma cells and de-differentiated melanoma cells. Importantly, within the same melanoma linage, the heterogeneity in lysosomal abundance underlies differential sensitivity to ferroptosis. To probe lysosomal function that controls ferroptosis sensitivity, we deleted a series of lysosome-related proteins and found that the lysosomal cysteine transporters CTNS and MFSD12 exert opposing effects on lysosomal de-differentiation and ferroptosis sensitivity. Specifically, deletion of the pH-dependent cystine exporter CTNS drives melanoma de-differentiation and promotes ferroptosis sensitivity while ablation of cysteine importer MFSD12 further enhances resistance to ferroptosis. On the other hand, while increasing lysosomal cystine export by overexpression of CTNS has moderate effects on melanoma de-differentiation, increasing lysosomal important by overexpression of MFSD12 results in melanoma de-differentiation and increases sensitivity to ferroptosis. Our findings suggest that disruption of lysosomal cysteine homeostasis is a key mechanism to drive melanoma de-differentiation which is accompanied by increased sensitivity to ferroptosis. Citation Format: Deyang Yu, Jiaxin Liang, Hans Widlund, Pere Puigserver. Lysosomal cyst(e)ine regulates melanoma de-differentiation and sensitivity to ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 279.