The lipogenic regulator SREBF2 induces Transferrin in circulating melanoma cells and suppresses ferroptosis [ChIP-Seq]

Circulating tumor cells (CTCs) are shed by cancer into the bloodstream, where a viable subset overcomes oxidative stress to initiate metastatic outgrowth. Here we show that CTCs from patients with BRAF-mutant melanoma coordinately upregulate both lipogenesis and iron homeostasis pathways. In clonally-derived cultures of melanoma CTCs these pathways are correlated with both intrinsic and acquired resistance to BRAF inhibitors. The lipogenesis regulator SREBF2 directly induces transcription of the iron carrier Transferrin (TF), reducing intracellular iron pools, reactive oxygen species (ROS) and lipid peroxidation, and conferring resistance to both BRAF inhibitors and inducers of ferroptosis. Knockdown of endogenous TF impairs tumor formation by melanoma CTCs, and their tumorigenic defects are partially rescued by the lipophilic anti-oxidants Ferrostatin-1 and Vitamin E. In a cohort of patient-derived melanoma CTCs, single cell RNA-seq identifies a subset with high lipogenic, iron metabolic and proliferative signatures, which are correlated with adverse clinical outcome, irrespective of treatment regimen. Thus, SREBF2-driven iron homeostatic pathways contribute to cancer progression, drug resistance and metastasis. Overall design: To identify SREBF2-regulated genes mediating tumor-enhancing effects of SREBF2 expression, we undertook chromatin immunoprecipitation followed by Next Generation Sequencing (ChIP-Seq), defining direct SREBF2 transcriptional targets in cultured melanoma CTCs.