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

Autor:	Koundouros N; Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Division of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK., Karali E; Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK., Tripp A; Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK., Valle A; Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Energy Metabolism and Nutrition, Research Institute of Health Sciences (IUNICS), University of Balearic Islands, 07122 Palma de Mallorca, Spain; Health Research Institute of the Balearic Islands (IdISBa), University of Balearic Islands, 07120 Palma de Mallorca, Spain; Biomedical Research Networking Center for Physiopathology of Obesity and Nutrition (CIBERobn CB06/03/0043), Instituto de Salud Carlos III, 28029 Madrid, Spain., Inglese P; Division of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK., Perry NJS; Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK., Magee DJ; Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Pain Medicine Department, The Royal Marsden Hospital, London, UK., Anjomani Virmouni S; Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK., Elder GA; Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, UK., Tyson AL; Flow Cytometry and Light Microscopy Core Facility, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, 25 Howland Street, London W1T 4JG, UK., Dória ML; Division of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK., van Weverwijk A; Breast Cancer Now Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Division of Tumor Biology and Immunology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands., Soares RF; Division of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK., Isacke CM; Breast Cancer Now Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK., Nicholson JK; Division of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK; The Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth WA6150, WA, Australia., Glen RC; Division of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK; Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK., Takats Z; Division of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK. Electronic address: z.takats@imperial.ac.uk., Poulogiannis G; Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK; Division of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK. Electronic address: george.poulogiannis@icr.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2020 Jun 25; Vol. 181 (7), pp. 1596-1611.e27. Date of Electronic Publication: 2020 Jun 18.
DOI:	10.1016/j.cell.2020.05.053
Abstrakt:	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. Competing Interests: Declaration of Interests N.K. and G.P. are inventors on a patent application covering new methods and compositions useful in the treatment of cancers with PIK3CA mutation (application number GB 2005874.9). (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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