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Cell adhesion and ferroptosis: investigating a potential vulnerability in cancer cells

细胞粘附和铁死亡：研究癌细胞的潜在脆弱性

基本信息

批准号：
10213635
负责人：
Alexander Michael Minikes
金额：
$ 4.6万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2022-07-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213635
关键词：
3-Dimensional Adherens Junction Adhesions Adhesives Affect Biological Markers Cadherin Domain Cadherins Cancer Patient Cancer cell line Cardiovascular system Cell Adhesion Cell Adhesion Molecules Cell Death Cell Line Cell surface Cells Cellular Membrane Characteristics Clinic Clinical Code Cultured Cells Data Databases Diet Diffuse Disseminated Malignant Neoplasm Distant E-Cadherin Embryo Environment Epithelial Cells Exclusion Exhibits Extracellular Domain Extracellular Matrix Family member Fibroblasts Future Gene Expression Genes Glutathione Homeostasis Homodimerization In Vitro Integrins Investigation Iron Lead Light Lipid Peroxidation Lipid Peroxides Location Malignant Neoplasms Mesenchymal Mesothelioma Metabolic Missense Mutation Modeling Monitor Mus Mutate Mutation N-Cadherin Necrosis Neoplasm Metastasis Nuclear Oncogenic Oxidation-Reduction Pathway interactions Pharmaceutical Preparations Phenotype Phospholipids Play Process Property Proteins RNA Interference Regulation Reporting Resistance Role Signal Pathway Site Solid Neoplasm TFRC gene Techniques Testing The Cancer Genome Atlas Transcription Coactivator Translating Travel Tumor Burden Up-Regulation Xenograft Model Xenograft procedure cancer cell cancer subtypes cancer type cell motility density gastric cancer cell in vivo malignant stomach neoplasm mouse model mutant overexpression phospholipid-hydroperoxide glutathione peroxidase reconstitution response small molecule subcutaneous tumor tumor growth

项目摘要

Project Summary Ferroptosis is a form of oxidative regulated necrosis caused by an inability of the phospholipid-targeting glutathione peroxidase GPx4 to detoxify lipid hydroperoxides. Recently, we found that E-cadherin homodimerization can regulate cell sensitivity to the induction of ferroptosis by inhibition of glutathione synthesis or GPx4 inhibition. Mechanistically, we found that this is due to crosstalk with the Hippo signaling pathway, which regulates the transcriptional co-activator YAP. YAP was found to regulate the expression of genes related to ferroptosis. E-cadherin, which is frequently mutated in gastric cancer, is an important suppressor of motility and thus metastasis in tumors. Intriguingly, cancer cells with a metastatic-like phenotype were found to be highly sensitive to ferroptosis, suggesting that the loss of E-cadherin or perhaps other adhesion molecules could play a role in regulating this process. As such, we would like to better understand the relationship cells, their environment, and sensitivity to ferroptosis using a variety of techniques, both in vitro and in vivo. First, we intend to determine whether common mutations to the E-cadherin gene found in cancer patients can render gastric cancer cells sensitive to ferroptosis. We would also like to determine whether this phenomenon is specific to E-cadherin, or a more general cell non- autonomous mechanism of regulation that coordinates with adjacent cells and the extracellular matrix. Finally, we would like to determine, in mouse models of gastric cancer, whether E-cadherin is a determinant for sensitivity to ferroptosis, and whether the induction of ferroptosis can reduce tumor growth and metastasis.

项目摘要铁凋亡是一种氧化调节性坏死的形式，磷脂靶向谷胱甘肽过氧化物酶GPx 4解毒脂质氢过氧化物。最近，我们发现E-钙粘蛋白同二聚化可以调节细胞对钙粘蛋白的敏感性通过抑制谷胱甘肽合成或GPx 4抑制诱导铁凋亡。从机制上讲，我们发现这是由于与Hippo信号通路的串扰，其调节转录辅激活因子雅普。发现雅普可调节铁凋亡相关基因的表达。E-钙粘蛋白，它经常突变，胃癌是肿瘤运动和转移的重要抑制因子。有趣的是，具有转移样表型的癌细胞被发现是高表达的。对铁凋亡敏感，这表明E-钙粘蛋白或其他蛋白的丢失可能导致细胞凋亡。粘附分子可能在调节这一过程中发挥作用。因此，我们希望为了更好地了解关系细胞，它们的环境，以及对使用各种技术，在体外和体内的铁凋亡。首先，我们打算确定在癌症患者中发现的E-钙粘蛋白基因的常见突变是否可使胃癌细胞对铁凋亡敏感。我们还想确定这种现象是否是E-钙粘蛋白所特有的，或者是更普遍的细胞非- 与相邻细胞协调的自主调节机制，细胞外基质最后，我们想确定，在小鼠胃模型中，癌症，E-钙粘蛋白是否是铁凋亡敏感性的决定因素，以及是否铁凋亡的诱导可以减少肿瘤的生长和转移。