Koundouros, NikosKarali, EvdoxiaTripp, AurelienValle, AdamoInglese, PaoloPerry, Nicholas JSMagee, David JVirmouni, Sara AnjomaniElder, George ATyson, Adam LDoria, Maria Luisavan Weverwijk, AntoinetteSoares, Renata FIsacke, Clare MNicholson, Jeremy KGlen, Robert CTakats, ZoltanPoulogiannis, George2024-09-132024-09-132020-06-25Koundouros N, Karali E, Tripp A, Valle A, Inglese P, Perry N, et al. Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids. Cell. 2020 Jun 25;181(7):1596-611. Epub 2020 Jun 18.0092-8674http://hdl.handle.net/20.500.13003/17241https://hdl.handle.net/20.500.12105/22874Oncogenic 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 'Knife 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-PKC zeta-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.enghttp://creativecommons.org/licenses/by-nc-nd/4.0/research articleAttribution-NonCommercial-NoDerivatives 4.0 International3255946118171596-161110.1016/j.cell.2020.05.0531097-4172Cellopen accessTransducción de SeñalAnimalesLínea Celular TumoralDiana Mecanicista del Complejo 2 de la RapamicinaFosfatidilinositol 3-QuinasasEicosanoidesRedes y Vías MetabólicasFemeninoÁcido AraquidónicoFosfolipasas A2Ensayos Antitumor por Modelo de XenoinjertoCitosolFosforilaciónActivación EnzimáticaHumanosMetabolismo de los LípidosFosfatidilinositol 3-Quinasa Clase IRatones Endogámicos BALB CProteína Quinasa CRatones Desnudos2-s2.0-85086742293543822100016L2006823274