Ferroptosis and Cancer Cell Signaling

铁性下垂与癌细胞信号转导 摘要 细胞程序性死亡(PCD)在正常生物学中起着重要作用，其去调控有助于 各种疾病的发展。铁下垂是一种由细胞代谢和铁驱动的PCD模式。 依赖于细胞的脂质过氧化。越来越多的证据表明，铁性下垂与多种疾病有关。 病理情况，包括癌症。因此，了解铁性下垂的发病机制是很重要的。 用于基础生物学和疾病治疗。 虽然大多数铁性上睑下垂的机制研究集中在细胞内分子事件上，但我们最近的 研究揭示了一种概念上新的铁下垂调节机制，即非细胞自主的： 上皮细胞，E-钙粘附素介导的细胞间相互作用通过细胞内抑制铁性下垂 Merlin/NF2-Hippo信号；拮抗该信号轴释放原癌基因的活性 转录共激活因子YAP通过调节多个铁下垂调节剂促进铁性下垂。作为E- 钙粘附素和Hippo-YAP信号是上皮间充质转化(EMT)的关键调节因子，我们的工作 为最近发表的间质和转移的观察提供了机械性的见解 癌细胞的特性与癌细胞对铁下垂诱导的敏感性高度相关。我们的 初步研究表明，上皮钙粘附素及其多种成分的恶性突变可能与骨肉瘤的发生有关。 河马-YAP信号通路可作为预测未来癌细胞反应性的生物标志物 铁性下垂的治疗方法。考虑到肿瘤抑制基因E-钙粘附素功能突变的丧失， NF2和LAT1/2(河马信号的组成部分)，以及YAP癌蛋白的超激活都是 恶性事件使癌细胞对常见疗法和凋亡细胞死亡更具抵抗力，我们的 研究发现，这些相同的突变反而使癌细胞对铁下垂的诱导更加敏感 在概念和临床上都是意想不到的和非常重要的。 在这些初步结果的基础上，在本方案中，(1)细胞间，我们将研究分子 E-钙粘附素在将信号传递到细胞内机制中的作用，从而发挥作用的基础 作为一种肿瘤抑制因子和一种反直觉的铁下垂抑制剂；为了进一步扩展这一概念，我们 将确定其他细胞黏附分子是否也可以通过类似的机制调节铁下垂；(2) 在细胞内，我们将确定YAP如何通过其转录共同调节来决定铁下垂的敏感性。 活性；以及(3)与癌症有关，因为E-钙粘素突变在胃癌这一致命疾病中非常频繁。 目前还没有有效的治疗方法，我们将研究E-钙粘素肿瘤抑制因子在确定 胃癌细胞对铁下垂的敏感性及E-钙粘附素调节的胃铁下垂的可能作用 癌症转移。基因工程小鼠的胃癌模型，以及胃癌患者- 衍生的肿瘤有机化合物和异种移植小鼠模型将用于这项临床前研究。已被占用 总之，拟议研究的成功将揭示铁性下垂的深入机制，以及它的 与各种与癌症相关的细胞间和细胞内分子事件的功能交流。这个 拟议的研究还将导致识别预测癌症对未来反应的生物标记物 铁性下垂诱发癌症的治疗。

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.