Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids
Graphical Abstract Highlights d The iKnife offers near real-time diagnosis of PIK3CA mutant breast cancers d Oncogenic PIK3CA promotes enhanced arachidonic acid via mTORC2-PKCz-cPLA2 signaling d Mutant PIK3CA regulates proliferation beyond a cell autonomous manner d 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
... ve 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-PKCz-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. ll OPEN ACCESS Cell . A novel methodology for in vivo endoscopic phenotyping of colorectal cancer based on real-time analysis of the mucosal lipidome: a prospective observational study of the iKnife. Surg. Endosc. 31, 1361-1370. Ambs, P., Baccarini, M., Fitzke, E., and Dieter, P. (1995). Role of cytosolic phospholipase A2 in arachidonic acid release of rat-liver macrophages: regulation by Ca2+ and phosphorylation. Biochem.