Pan-cancer transcriptional signatures predictive of oncogenic mutations reveal that Fbw7 regulates cancer cell oxidative metabolism
Menée à partir de données issues du projet "The Cancer Genome Atlas", puis à l'aide de lignées cellulaires de cancer colorectal, cette étude met en évidence des mécanismes par lesquels, en induisant une reprogrammation métabolique, des mutations du gène de l'ubiquitine ligase Fbw7 favorisent la tumorigenèse
Tumor suppression by the Fbw7 ubiquitin ligase remains poorly understood. Here, we used informatics and engineered cancer cells to show that Fbw7 mutations cause metabolic reprogramming by increasing oxidative phosphorylation and metabolic vulnerabilities that may represent therapeutic targets. Our approach may be applied to study other complex cancer genes. The Fbw7 (F-box/WD repeat-containing protein 7) ubiquitin ligase targets multiple oncoproteins for degradation and is commonly mutated in cancers. Like other pleiotropic tumor suppressors, Fbw7’s complex biology has impeded our understanding of how Fbw7 mutations promote tumorigenesis and hindered the development of targeted therapies. To address these needs, we employed a transfer learning approach to derive gene-expression signatures from The Cancer Gene Atlas datasets that predict Fbw7 mutational status across tumor types and identified the pathways enriched within these signatures. Genes involved in mitochondrial function were highly enriched in pan-cancer signatures that predict Fbw7 mutations. Studies in isogenic colorectal cancer cell lines that differed in Fbw7 mutational status confirmed that Fbw7 mutations increase mitochondrial gene expression. Surprisingly, Fbw7 mutations shifted cellular metabolism toward oxidative phosphorylation and caused context-specific metabolic vulnerabilities. Our approach revealed unexpected metabolic reprogramming and possible therapeutic targets in Fbw7-mutant cancers and provides a framework to study other complex, oncogenic mutations.