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

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-cadherin同源二聚体化可以调节细胞对 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。

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.