TFE3 fusion proteins drive oxidative metabolism, ferroptosis resistance and general RNA synthesis in translocation renal cell carcinoma

The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterised. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome at H3K27ac-marked active chromatin, engaging a core set of M/E-box-containing regulatory elements to activate specific gene expression programs as well as promiscuous binding to active promoters to stimulate mRNA synthesis. Within the core program, TFE3 fusions directly regulate genes involved in ferroptosis resistance and oxidative phosphorylation metabolism (OxPhos) increasing functional OxPhos levels. Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). We further show that tRCC tumour aggressiveness is related to their EMT which although enriched in tumours harbouring ASPSCR1-TFE3 fusions, is also a frequent feature of tumours harbouring other TFE3 fusions. In tRCC tumours, the presence of mesenchymal tRCC cancer cells associates with that of myofibroblast cancer-associated fibroblasts (myCAFs) that are both hallmarks of poor prognostic outcomes. We define tRCC as a novel metabolic subtype of renal cancer and provide unique insights into how broad genomic binding of TFE3 fusion proteins regulates OxPhos and ferroptosis resistance and more generally stimulates RNA synthesis.