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

Ryan J. Davis, Mehmet Gönen, Daciana H. Margineantu, Shlomo Handeli, Jherek Swanger, Pia Hoellerbauer, Patrick J. Paddison, Haiwei Gu, Daniel Raftery, Jonathan E. Grim, David M. Hockenbery, Adam A. Margolin, Bruce E. Clurman

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5462-5467
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number21
DOIs
StatePublished - May 22 2018

Keywords

  • Fbw7
  • Genomics
  • Informatics
  • Metabolism
  • Ubiquitin

ASJC Scopus subject areas

  • General

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    Davis, R. J., Gönen, M., Margineantu, D. H., Handeli, S., Swanger, J., Hoellerbauer, P., Paddison, P. J., Gu, H., Raftery, D., Grim, J. E., Hockenbery, D. M., Margolin, A. A., & Clurman, B. E. (2018). Pan-cancer transcriptional signatures predictive of oncogenic mutations reveal that Fbw7 regulates cancer cell oxidative metabolism. Proceedings of the National Academy of Sciences of the United States of America, 115(21), 5462-5467. https://doi.org/10.1073/pnas.1718338115