小柯机器人

英国癌症研究所George Poulogiannis和伦敦帝国理工学院Zoltan Takats研究小组合作取得一项新成果。他们利用代谢指纹图谱将致癌PIK3CA与花生四烯酸衍生的类花生酸联系起来。这一研究成果在线发表在2020年6月18日的《细胞》上。

使用iKnife采样烧灼标本的气溶胶，研究人员展示了一种实时诊断的新方法，其将代谢表型与PIK3CA基因突变体耦合。致癌PIK3CA导致花生四烯酸增加和类花生酸的过量生产，从而以超出细胞自主的方式促进细胞增殖。从机理上讲，突变体PIK3CA促进了一个多模式信号网络，该网络涉及mTORC2-PKCζ介导的钙依赖性磷脂酶A2（cPLA2）的活化。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降低突变体PIK3CA诱导的致瘤性。

除了证明其在分层医学中代谢表型的应用潜力外，本研究还揭示了活化的PI3K信号传导在调节花生四烯酸代谢中的重要作用，并揭示了主要取决于饮食脂肪限制的可靶向代谢脆弱性。

据了解，致癌转化与细胞代谢的变化有关，但是，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。

附：英文原文

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

Author: Nikos Koundouros, Evdoxia Karali, Aurelien Tripp, Adamo Valle, Paolo Inglese, Nicholas J.S. Perry, David J. Magee, Sara Anjomani Virmouni, George A. Elder, Adam L. Tyson, Maria Luisa Dória, Antoinette van Weverwijk, Renata F. Soares, Clare M. Isacke, Jeremy K. Nicholson, Robert C. Glen, Zoltan Takats, George Poulogiannis

Issue&Volume: 2020-06-18

Abstract: 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.

DOI: 10.1016/j.cell.2020.05.053

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30686-3