The lipogenic regulator SREBF2 induces Transferrin in circulating melanoma cells and suppresses ferroptosis [CTC lines vs tumors and CCLE lines RNA-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. We generated five patient-derived CTC cultures following microfluidic enrichment of blood samples from four patients with metastatic melanoma. We generated RNA-Seq profiles of 13 biological replicates from the five cultures. We also generated two RNA-Seq profiles from archival primary tumor specimens from one of the four patients and generated six profiles from archival independent metastatic lesions from another of the four patients. We compared the 13 RNA-seq profiles to those of standard melanoma tumor-derived cell lines (Cancer Cell Line Encyclopedia; CCLE; PMID: 22460905), and primary and metastatic melanoma tumors (The Cancer Genome Atlas; TCGA; PMID: 26091043), all generated by the same computational pipeline. We also compared the profiles of the primary and metastatic tumor specimens with the profiles of the matched CTC culture samples.