Journal article
Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids
Cell, Vol.181(7), pp.1596-1611.e27
2020
Abstract
Oncogenic transformation is associated with profound changes in cellular metabolism, but whether tracking these can improve disease stratification or influence therapy decision-making is largely unknown. Using the iKnife to sample the aerosol of cauterized specimens, we demonstrate a new mode of real-time diagnosis, coupling metabolic phenotype to mutant PIK3CA genotype. Oncogenic PIK3CA results in an increase in arachidonic acid and a concomitant overproduction of eicosanoids, acting to promote cell proliferation beyond a cell-autonomous manner. Mechanistically, mutant PIK3CA drives a multimodal signaling network involving mTORC2-PKCζ-mediated activation of the calcium-dependent phospholipase A2 (cPLA2). Notably, inhibiting cPLA2 synergizes with fatty acid-free diet to restore immunogenicity and selectively reduce mutant PIK3CA-induced tumorigenicity. Besides highlighting the potential for metabolic phenotyping in stratified medicine, this study reveals an important role for activated PI3K signaling in regulating arachidonic acid metabolism, uncovering a targetable metabolic vulnerability that largely depends on dietary fat restriction.
Details
- Title
- Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids
- Authors/Creators
- N. Koundouros (Author/Creator)E. Karali (Author/Creator)A. Tripp (Author/Creator)A. Valle (Author/Creator)P. Inglese (Author/Creator)N.J.S. Perry (Author/Creator)D.J. Magee (Author/Creator)S. Anjomani Virmouni (Author/Creator)G.A. Elder (Author/Creator)A.L. Tyson (Author/Creator)M.L. Dória (Author/Creator)A. van Weverwijk (Author/Creator)R.F. Soares (Author/Creator)C.M. Isacke (Author/Creator)J.K. Nicholson (Author/Creator)R.C. Glen (Author/Creator)Z. Takats (Author/Creator)G. Poulogiannis (Author/Creator)
- Publication Details
- Cell, Vol.181(7), pp.1596-1611.e27
- Publisher
- Elsevier Inc.
- Identifiers
- 991005545467207891
- Copyright
- © 2020 The Author(s).
- Murdoch Affiliation
- Australian National Phenome Centre; Health Futures Institute
- Language
- English
- Resource Type
- Journal article
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- 1 Clinical & Life Sciences
- 1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis
- 1.25.1473 Warburg Effect
- Web Of Science research areas
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