Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids.
Embargo End Date
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
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
Document Type
Journal Article
Date
2020-06-25
Date Accepted
2020-05-28
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.
Citation
Cell, 2020, 181 (7), pp. 1596 - 1611.e27
Source Title
Publisher
CELL PRESS
ISSN
0092-8674
eISSN
1097-4172
Collections
Research Team
Molecular Cell Biology
Signalling & Cancer Metabolism
Signalling & Cancer Metabolism