Helleux Alexandra, Davidson Guillaume, Lallement Antonin, Hourani Fatima Al, Haller Alexandre, Michel Isabelle, Fadloun Anas, Thibault-Carpentier Christelle, Su Xiaoping, Lindner Véronique, Tricard Thibault, Lang Hervé, Tannir Nizar M, Davidson Irwin, Malouf Gabriel G
Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, 67404, Illkirch, France.
EMBO Mol Med. 2025 May;17(5):1041-1070. doi: 10.1038/s44321-025-00221-7. Epub 2025 Mar 27.
The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterized. 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). Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). We further show that tRCC tumor aggressiveness is related to their EMT and their associated enrichment in 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.
TFE3融合蛋白驱动易位性肾细胞癌（tRCC）的致癌机制目前尚不清楚。在此，我们在tRCC细胞系和患者肿瘤中，将功能缺失和功能获得实验与多组学分析相结合。NONO-TFE3或PRCC-TFE3融合蛋白的高核积累促进它们在全基因组中与H3K27ac标记的活性染色质广泛结合，与一组包含M/E盒的核心调控元件结合，以激活特定的基因表达程序，并与活性启动子发生混杂结合以刺激mRNA合成。在核心程序中，TFE3融合蛋白直接调控参与铁死亡抗性和氧化磷酸化代谢（OxPhos）的基因。因此，人类tRCC肿瘤显示出高OxPhos评分，且在其上皮-间质转化（EMT）过程中持续存在。我们进一步表明，tRCC肿瘤的侵袭性与其EMT以及肌成纤维细胞癌相关成纤维细胞（myCAF）中的相关富集有关，而这两者都是预后不良的标志。我们将tRCC定义为一种新型的肾癌代谢亚型，并对TFE3融合蛋白的广泛基因组结合如何调节OxPhos和铁死亡抗性提供了独特的见解。
