E-cadherin-deficient cells have synthetic lethal vulnerabilities in plasma membrane organisation, dynamics and function.
E-cadherin-deficient cells have synthetic lethal vulnerabilities in plasma membrane organisation, dynamics and function.
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E-钙粘蛋白缺陷型细胞在质膜组织，动力学和功能中具有合成的致命性脆弱性。
DOI：
10.1007/s10120-018-0859-1
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Guilford PJ
中科院分区：
文献类型：
--
作者：
Godwin TD;Kelly ST;Brew TP;Bougen-Zhukov NM;Single AB;Chen A;Stylianou CE;Harris LD;Currie SK;Telford BJ;Beetham HG;Evans GB;Black MA;Guilford PJ
E-钙粘蛋白基因(CDH1)在弥漫性胃癌和小叶性乳腺癌中经常发生突变，胚系突变易发生癌综合征遗传性弥漫性胃癌。我们正在采取一种合成致命的方法来确定CDH1突变癌症中的可药物脆弱性。通过对MCF10A和MCF10A-CDH1−/−细胞进行全基因组RNA干扰筛选，细胞活性数据的密度分布被用来识别受CDH1突变影响的蛋白质类别。通过同基因乳腺MCF10A细胞和CDH1-等基因胃NCI-N87细胞的药物敏感性分析，确定了选定的蛋白质类别与E-钙粘附素之间的合成致死关系。内吞效率用霍乱毒素B摄取率来量化。415例TCGA胃癌中通路Metagene的表达与CDH1的表达有统计学相关性。MCF10A-CDH1−/−细胞对PI3K/AKT途径、GPCRs、离子通道、蛋白酶体亚单位蛋白和泛素化酶等基因的敏感性发生了显著变化。MCF10A-CDH1−/−和NCI-N87-CDH1−/−细胞对破坏质膜组成和运输的化合物比野生型细胞更敏感，但对肌动蛋白聚合抑制剂和氯通道抑制剂NS3728的敏感性相反。MCF10A-CDH1−/−细胞株对内吞霍乱毒素B的能力降低。路径元基因分析确定了20条在肿瘤中可能合成致命的反应组途径。在候选的合成致死基因中，参与GPCR信号转导、囊泡运输以及PI3K和膜脂代谢的基因具有很强的代表性。E-钙粘附素的丢失导致受体信号和质膜运输和组织的紊乱，造成可用药的脆弱性。这篇文章的在线版本(10.1007/s10120-0180859-1)包含补充材料，授权用户可以使用。
The E-cadherin gene (CDH1) is frequently mutated in diffuse gastric cancer and lobular breast cancer, and germline mutations predispose to the cancer syndrome Hereditary Diffuse Gastric Cancer. We are taking a synthetic lethal approach to identify druggable vulnerabilities in CDH1-mutant cancers. Density distributions of cell viability data from a genome-wide RNAi screen of isogenic MCF10A and MCF10A-CDH1−/− cells were used to identify protein classes affected by CDH1 mutation. The synthetic lethal relationship between selected protein classes and E-cadherin was characterised by drug sensitivity assays in both the isogenic breast MCF10A cells and CDH1-isogenic gastric NCI-N87. Endocytosis efficiency was quantified using cholera toxin B uptake. Pathway metagene expression of 415 TCGA gastric tumours was statistically correlated with CDH1 expression. MCF10A-CDH1−/− cells showed significantly altered sensitivity to RNAi inhibition of groups of genes including the PI3K/AKT pathway, GPCRs, ion channels, proteosomal subunit proteins and ubiquitinylation enzymes. Both MCF10A-CDH1−/− and NCI-N87-CDH1−/− cells were more sensitive than wild-type cells to compounds that disrupted plasma membrane composition and trafficking, but showed contrasting sensitivities to inhibitors of actin polymerisation and the chloride channel inhibitor NS3728. The MCF10A-CDH1−/− cell lines showed reduced capacity to endocytose cholera toxin B. Pathway metagene analysis identified 20 Reactome pathways that were potentially synthetic lethal in tumours. Genes involved in GPCR signalling, vesicle transport and the metabolism of PI3K and membrane lipids were strongly represented amongst the candidate synthetic lethal genes. E-cadherin loss leads to disturbances in receptor signalling and plasma membrane trafficking and organisation, creating druggable vulnerabilities. The online version of this article (10.1007/s10120-018-0859-1) contains supplementary material, which is available to authorised users.
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