Koundouros, N;
Karali, E;
Tripp, A;
Valle, A;
Inglese, P;
Perry, NJS;
Magee, DJ;
... Poulogiannis, G; + view all
(2020)
Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids.
Cell
, 181
(7)
1596-1611.e27.
10.1016/j.cell.2020.05.053.
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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. VIDEO ABSTRACT.
| Type: | Article |
|---|---|
| Title: | Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.cell.2020.05.053 |
| Publisher version: | https://doi.org/10.1016/j.cell.2020.05.053 |
| Language: | English |
| Additional information: | This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | PIK3CA, PKCζ, arachidonic acid, cPLA2, cancer metabolism, diet, eicosanoids, fat restriction, iKnife, mTORC2 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > The Sainsbury Wellcome Centre |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10105198 |
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