Abstract 6073: The lipogenic regulator SREBP induces Transferrin in circulating melanoma cells, suppressing their susceptibility to ferroptosis

Circulating tumor cells (CTCs) are shed by cancers into the bloodstream, where a viable subset overcomes oxidative stress to initiate metastatic outgrowth. Clonally derived cultured CTCs from patients with BRAF-mutant melanoma reveal upregulation of lipogenesis and iron homeostasis pathways, correlated with their baseline and acquired drug resistance. In CTCs, the lipogenesis regulator SREBP directly induces transcription of the iron carrier Transferrin (TF), thereby reducing intracellular reactive oxygen species (ROS) and lipid peroxidation, and conferring resistance to BRAF inhibitors and inducers of ferroptosis. Knockdown of endogenous TF impairs tumorigenesis by melanoma CTCs; their associated soft agar clonogenic defect is rescued by the lipophilic anti-oxidants Ferrostatin-1 or Vitamin E, and by cholesterol. Single cell RNA-seq of patient-derived melanoma CTCs identifies a subset with high lipogenic, iron metabolic and proliferative signatures, correlated with adverse clinical outcome. Together, the coordinated regulation of these SREBP-driven pathways contributes to cancer progression, drug resistance and metastasis. Citation Format: Xin Hong, Whijae Roh, Ryan J. Sullivan, Keith H. Wong, Ben S. Wittner, HongShan Guo, Taronish D. Dubash, Moshe Sade-Feldman, Ben K. Wesley, Genevieve M. Boland, Dieuwke L. Marvin, Todd Bonesteel, Chenyue Lu, Elad Horwitz, François Aguet, Samuel S. Freeman, Katherine Calhoun, Michelle K. Jewett, Linda T. Nieman, Nir Hacohen, Anders M. Näär, David T. Ting, Mehmet Toner, Shannon L. Stott, Gad Getz, Shyamala Maheswaran, Daniel A. Haber. The lipogenic regulator SREBP induces Transferrin in circulating melanoma cells, suppressing their susceptibility to ferroptosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6073.