학술논문
Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids
Document Type
Report
Author
Koundouros, Nikos; Karali, Evdoxia; Tripp, Aurelien; Valle, Adamo; Inglese, Paolo; Perry, Nicholas J.S.; Magee, David J.; Anjomani Virmouni, Sara; Elder, George A.; Tyson, Adam L.; Doria, Maria Luisa; van Weverwijk, Antoinette; Soares, Renata F.; Isacke, Clare M.; Nicholson, Jeremy K.; Glen, Robert C.; Takats, Zoltan; Poulogiannis, George
Source
Cell. June 25, 2020, Vol. 181 Issue 7, 1596
Subject
Language
English
ISSN
0092-8674
Abstract
Keywords PIK3CA; mTORC2; PKC[zeta]; cPLA2; arachidonic acid; eicosanoids; iKnife; fat restriction; diet; cancer metabolism Highlights * The iKnife offers near real-time diagnosis of PIK3CA mutant breast cancers * Oncogenic PIK3CA promotes enhanced arachidonic acid via mTORC2-PKC[zeta]-cPLA2 signaling * Mutant PIK3CA regulates proliferation beyond a cell autonomous manner * cPLA2 inhibition and dietary fat restriction suppress PIK3CA-induced tumorigenicity Summary 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-PKC[zeta]-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. Video Abstract Display Omitted