1. Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids
- Author
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Koundouros, N., Karali, E., Tripp, A., Valle, A., Inglese, P., Perry, N.J.S., Magee, D.J., Anjomani Virmouni, S., Elder, G.A., Tyson, A.L., Dória, M.L., van Weverwijk, A., Soares, R.F., Isacke, C.M., Nicholson, J.K., Glen, R.C., Takats, Z., Poulogiannis, G., Koundouros, N., Karali, E., Tripp, A., Valle, A., Inglese, P., Perry, N.J.S., Magee, D.J., Anjomani Virmouni, S., Elder, G.A., Tyson, A.L., Dória, M.L., van Weverwijk, A., Soares, R.F., Isacke, C.M., Nicholson, J.K., Glen, R.C., Takats, Z., and Poulogiannis, G.
- 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.
- Published
- 2020