Ferroptosis and Cancer Cell Signaling

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Ferroptosis and Cancer Cell Signaling Summary Programmed cell death (PCD) plays important role in normal biology, and its deregulation contributes to the development of various diseases. Ferroptosis is a PCD modality driven by cellular metabolism and iron- dependent cellular lipid peroxidation. Mounting evidence indicates that ferroptosis is involved in multiple pathological conditions, including cancer. Therefore, understanding the mechanisms of ferroptosis is important for both fundamental biology and disease treatment. While most mechanistic investigation of ferroptosis focuses on intracellular molecular events, our recent studies revealed a conceptually novel mechanism for ferroptosis regulation that is non-cell autonomous: in epithelial cells, E-cadherin-mediated intercellular interaction suppresses ferroptosis through intracellular Merlin/NF2-Hippo signaling; antagonizing this signaling axis unleashes the activity of the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis through regulating multiple ferroptosis modulators. As E- cadherin and Hippo-YAP signaling are key regulators of epithelial mesenchymal transition (EMT), our work provides mechanistic insights into the recently published observation that mesenchymal and metastatic properties of cancer cells are highly correlated with the sensitivity of cancer cells to ferroptosis induction. Our preliminary studies furthersuggest that malignant mutation of E-cadherin and multiple components in the Merlin- Hippo-YAP signaling pathway can be used as biomarkers predicting cancer cell responsiveness to future ferroptosis-inducing therapies. Considering that loss of function mutations of tumor suppressors E-cadherin, NF2, and Lat1/2 (components of Hippo signaling), as well as super-activation of YAP oncoprotein, are all malignant events that make cancer cells more resistant to common therapies and to apoptotic cell death, our finding that these same mutations instead render cancer cells more sensitive to ferroptosis induction is unexpected and highly important both conceptually and clinically. Based on these preliminary results, in this proposal, (1) intercellularly, we will investigate the molecular basis underlying the role of E-cadherin in transducing signals into the intracellular machinery, thus functioning as both a tumor suppressor and counter-intuitively, an inhibitor of ferroptosis; to further expand this concept, we will determine if other cell adhesion molecules can also regulate ferroptosis via similar mechanism; (2) intracellularly, we will determine how YAP dictates ferroptosis sensitivity via its transcription co-regulating activity; and (3) relevant to cancer, as E-cadherin mutation is highly frequent in gastric cancer, a fatal disease currently without effective treatment, we will investigate the role of E-cadherin tumor suppressor in determining gastric cancer cell sensitivity to ferroptosis, and the potential role of E-cadherin-regulated ferroptosis in gastric cancer metastasis. Genetically engineered mouse models for gastric cancer, as well as gastric cancer patient- derived tumor organoids and xenograft mouse models, will be used for this preclinical investigation. Taken together, success of the proposed research will unveil in-depth mechanisms of ferroptosis, as well as its functional communication with various cancer-relevant intercellular and intracellular molecular events. The proposed research will also lead to the identification of biomarkers that predict cancer responsiveness to future ferroptosis-inducing cancer therapy.