Metabolic fingerprinting links oncogenic PIK3CA with enhanced arachidonic acid-derived eicosanoids
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2020-06-25
Date Acceptance
2020-05-28
Citation
Cell, 2020, 181 (7), pp.1596-1611.e27
ISSN
0092-8674
Publisher
Elsevier
Start Page
1596
End Page
1611.e27
Journal / Book Title
Cell
Volume
181
Issue
7
Copyright Statement
© 2020 The Author(s). Published by Elsevier Inc.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000543822100016&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
CYTOSOLIC PHOSPHOLIPASE A(2)
MASS-SPECTROMETRY
BREAST-CANCER
PATHWAY
3-KINASE
GROWTH
INHIBITOR
ACTIVATION
DISCOVERY
MUTATION
Publication Status
Published
Date Publish Online
2020-06-18