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.
Metastatic cancer is the result of cells shedding their adhesions to the surrounding environment and escaping their primary site, traveling to distant locations throughout the body via the circulatory system. We have identified a potential vulnerability in these cells that have lost adhesive molecules on the cell surface, as they are rendered extremely sensitive to compounds that induce ferroptosis, a form of oxidative cell death, with remarkably high selectivity. The proposed study intends to determine whether this property of cells can serve as a marker for future treatments that can induce ferroptosis.