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http://bura.brunel.ac.uk/handle/2438/21067
Title: | Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids |
Authors: | Koundouros, N Karali, E Tripp, A Valle, A Inglese, P Perry, NJS Magee, DJ Anjomani Virmouni, S Elder, GA Tyson, AL Dória, ML van Weverwijk, A Soares, RF Isacke, CM Nicholson, JK Glen, RC Takats, Z Poulogiannis, G |
Keywords: | PIK3CA;mTORC2;PKCζ;cPLA2;arachidonic acid;eicosanoids |
Issue Date: | 25-Jun-2020 |
Publisher: | Elsevier BV |
Citation: | 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. (2020) 'Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids', Cell, 181 (7), 1596 - 1611.e27. doi: 10.1016/j.cell.2020.05.053. |
Abstract: | © 2020 The Author(s). 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-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. |
URI: | https://bura.brunel.ac.uk/handle/2438/21067 |
DOI: | https://doi.org/10.1016/j.cell.2020.05.053 |
ISSN: | 0092-8674 |
Appears in Collections: | Dept of Life Sciences Research Papers |
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