Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids
| العنوان: | Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids |
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| المؤلفون: | Robert C. Glen, Maria Luisa Dória, Paolo Inglese, Jeremy K. Nicholson, George A. Elder, Nikos Koundouros, Clare M. Isacke, Aurelien Tripp, Nicholas J. S. Perry, Adamo Valle, George Poulogiannis, Renata F. Soares, David J. Magee, Adam L. Tyson, Zoltan Takats, Antoinette van Weverwijk, Evdoxia Karali, Sara Anjomani Virmouni |
| المساهمون: | INSERM, Université de Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192, Imperial College London, The institute of cancer research [London], Glen, Robert [0000-0003-1759-2914], Apollo - University of Cambridge Repository, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille) |
| المصدر: | 1611.e27 Cell Cell, 2020, 181 (7), pp.1596-1611.e27. ⟨10.1016/j.cell.2020.05.053⟩ Clin Chem |
| بيانات النشر: | Elsevier BV, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Mutant, humanos, cancer metabolism, medicine.disease_cause, mTORC2, Translational Research, Biomedical, PATHWAY, ACTIVATION, chemistry.chemical_compound, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Cytosol, Phosphorylation, Overproduction, fosfatidil inositol 3 cinasas, MUTATION, redes y vías metabólicas, iKnife, 11 Medical and Health Sciences, Protein Kinase C, 0303 health sciences, Mutation, Mice, Inbred BALB C, biology, Immunogenicity, INHIBITOR, línea celular, 3-KINASE, Cell biology, fosfatidilinositol 3-cinasas de clase I, Perspective, GROWTH, citosol, Arachidonic acid, Female, Life Sciences & Biomedicine, fosforilación, Metabolic Networks and Pathways, Signal Transduction, Biochemistry & Molecular Biology, cPLA2, transducción de señales, Class I Phosphatidylinositol 3-Kinases, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mechanistic Target of Rapamycin Complex 2, General Biochemistry, Genetics and Molecular Biology, Article, eicosanoids, Cell Line, 03 medical and health sciences, Phospholipase A2, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], proteína cinasa C, Cell Line, Tumor, medicine, arachidonic acid, BREAST-CANCER, Animals, Humans, eicosanoides, 030304 developmental biology, PKCζ, Science & Technology, Cell growth, CYTOSOLIC PHOSPHOLIPASE A(2), Cell Biology, MASS-SPECTROMETRY, PIK3CA, 06 Biological Sciences, Lipid Metabolism, Xenograft Model Antitumor Assays, fosfolipasas A2, ensayos antitumorales por modelo de xenoinjerto, Enzyme Activation, fat restriction, Phospholipases A2, chemistry, activación enzimática, DISCOVERY, biology.protein, animales, metabolismo lipídico, ácido araquidónico, ratones, diet, 030217 neurology & neurosurgery, Developmental Biology |
| الوصف: | 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 Graphical Abstract Highlights • The iKnife offers near real-time diagnosis of PIK3CA mutant breast cancers • Oncogenic PIK3CA promotes enhanced arachidonic acid via mTORC2-PKCζ-cPLA2 signaling • Mutant PIK3CA regulates proliferation beyond a cell autonomous manner • cPLA2 inhibition and dietary fat restriction suppress PIK3CA-induced tumorigenicity Metabolic fingerprinting using the iKnife offers near real-time diagnosis of PIK3CA mutant breast cancers and connects oncogenic PIK3CA with enhanced arachidonic acid metabolism. cPLA2 inhibition shows remarkable synergy with dietary fat restriction to restore tumoral immune cell infiltration and inhibit growth of mutant PIK3CA-bearing breast tumors. |
| وصف الملف: | application/pdf; application/octet-stream; application/rdf+xml; charset=utf-8 |
| اللغة: | English |
| تدمد: | 0092-8674 1097-4172 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::90fa130c7ff6980499d408b016c615ff https://bura.brunel.ac.uk/handle/2438/21067 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....90fa130c7ff6980499d408b016c615ff |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00928674 10974172 |
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