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

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Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids.
Cell ( IF 45.5 ) Pub Date : 2020-06-18 , DOI: 10.1016/j.cell.2020.05.053
Nikos Koundouros ₁ , Evdoxia Karali ₂ , Aurelien Tripp ₂ , Adamo Valle ₃ , Paolo Inglese ₄ , Nicholas J S Perry ₂ , David J Magee ₅ , Sara Anjomani Virmouni ₆ , George A Elder ₇ , Adam L Tyson ₈ , Maria Luisa Dória ₄ , Antoinette van Weverwijk ₉ , Renata F Soares ₄ , Clare M Isacke ₁₀ , Jeremy K Nicholson ₁₁ , Robert C Glen ₁₂ , Zoltan Takats ₄ , George Poulogiannis ₁

Affiliation

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.
Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
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.
Division of Systems Medicine, Department of Metabolism Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK.
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.
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.
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.
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.
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.
Breast Cancer Now Research Centre, 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; The Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth WA6150, WA, Australia.
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.

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.

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中文翻译：

代谢指纹图谱将致癌 PIK3CA 与增强型花生四烯酸衍生的类二十烷酸联系起来。

致癌转化与细胞代谢的深刻变化相关，但追踪这些变化是否可以改善疾病分层或影响治疗决策尚不清楚。使用 iKnife 对烧灼标本的气溶胶进行采样，我们展示了一种新的实时诊断模式，将代谢表型与突变PIK3CA基因型耦合。致癌性PIK3CA导致花生四烯酸增加，并伴随类二十烷酸过量产生，从而促进细胞增殖，超出细胞自主方式。从机制上讲，突变型PIK3CA驱动多模式信号网络，涉及 mTORC2-PKC z 介导的钙依赖性磷脂酶 A2 (cPLA2) 激活。值得注意的是，抑制 cPLA2 与无脂肪酸饮食协同作用，可恢复免疫原性并选择性减少突变PIK3CA诱导的致瘤性。除了强调分层医学中代谢表型分析的潜力外，这项研究还揭示了激活的 PI3K 信号在调节花生四烯酸代谢中的重要作用，揭示了很大程度上取决于饮食脂肪限制的可靶向代谢脆弱性。

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更新日期：2020-06-25

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