Pan-cancer transcriptional signatures predictive of oncogenic mutations reveal that Fbw7 regulates cancer cell oxidative metabolism Article

Davis, RJ, Gönen, M, Margineantu, DH et al. (2018). Pan-cancer transcriptional signatures predictive of oncogenic mutations reveal that Fbw7 regulates cancer cell oxidative metabolism . 115(21), 5462-5467. 10.1073/pnas.1718338115

cited authors

  • Davis, RJ; Gönen, M; Margineantu, DH; Handeli, S; Swanger, J; Hoellerbauer, P; Paddison, PJ; Gu, H; Raftery, D; Grim, JE; Hockenbery, DM; Margolin, AA; Clurman, BE

fiu authors

abstract

  • 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.

publication date

  • May 22, 2018

Digital Object Identifier (DOI)

start page

  • 5462

end page

  • 5467

volume

  • 115

issue

  • 21