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

项目摘要 铁性下垂是氧化调节性坏死的一种形式，其原因是 磷脂靶向谷胱甘肽过氧化物酶Gpx4解毒脂质过氧化氢。 最近，我们发现E-钙粘素同源二聚化可以调节细胞对 通过抑制谷胱甘肽合成或抑制Gpx4诱导铁性下垂。 从机制上讲，我们发现这是由于与河马信号通路的串扰， 该基因调控转录共激活因子YAP。YAP被发现调节了 铁性下垂相关基因的表达。E-钙粘附素，它经常在 胃癌是一种重要的运动抑制因子，因此在肿瘤转移中起重要作用。 有趣的是，具有转移样表型的癌细胞被发现高度 对铁性下垂敏感，提示E-钙粘附素的丢失或其他 黏附分子可能在调节这一过程中发挥作用。因此，我们希望 为了更好地了解细胞之间的关系、它们的环境和对 使用各种技术的铁下垂，包括体外和体内。首先，我们打算 确定在癌症患者中发现的E-钙粘素基因的常见突变 可使胃癌细胞对铁下垂敏感。我们还想确定 无论这种现象是E-钙粘素所特有的，还是更一般的细胞非 自主调节机制，与相邻细胞和 细胞外基质。最后，我们想确定，在小鼠的胃部模型中 癌症，E-钙粘附素是否是铁下垂敏感性的决定因素，以及 铁性下垂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.