Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids

Abstract

Summary 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

RETRACTED ARTICLE: Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

“…In addition to MS, the increase in AA release and its metabolism to prostaglandins and leukotrienes have been observed in cancers and other neurodegeneration diseases [ 49 – 51 ]. For example, PIK3CA mutant breast cancer tumor cells displayed dramatically elevated AA and eicosanoid levels, promoting tumor cell proliferation [ 50 ].…”

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“…Oncogenic PIK3CA (encoding a PI3K isoform) results in an increase of AA and eicosanoids, thus promoting cell proliferation to beyond a cell-autonomous degree. Mechanistically, mutant PIK3CA drives a multimodal signaling network involving mTORC2-PKCζ-mediated activation of cPLA 2 α [ 89 ]. Notably, inhibition of cPLA 2 α acts synergistically with a fatty acid-free diet to restore immunogenicity and selectively reduce mutant PIK3CA-induced tumorigenicity.…”

The hallmarks of cancer are also the hallmarks of wound healing

“…Positron emission tomography (PET) scanning in the clinic takes advantage of this phenomenon because cancer cells primarily using glycolysis are much more demanding of glucose than are healthy cells primarily generating energy through oxidative phosphorylation, and so radioactively tagged glucose highlights cancer cells within tissues (113). This altered metabolic signature can even be used to guide a surgeon's iKnife for excising the margins of a tumor (114).…”