美国纪念斯隆凯特琳癌症中心姜学军和中国空军医科大学陈志南研究团队合作取得一项新进展。他们的研究发现细胞间相互作用通过NF2-YAP信号影响癌细胞铁死亡。相关论文于2019年8月15日发表于国际学术期刊《自然》上。

研究人员发现，铁死亡可以通过钙粘蛋白介导的细胞间相互作用进行非细胞自主调控。在上皮细胞中，由E-钙粘蛋白介导的这种相互作用通过激活细胞内NF2（也称为merlin）和Hippo信号传导途径来抑制铁死亡。拮抗该信号轴使得原癌基因转录共激活因子YAP通过上调几种铁死亡调节蛋白（包括ACSL4和TFRC）来促进铁死亡。这一发现为具有间充质或转移性癌细胞对铁死亡高度敏感的观察结果提供了机制见解。值得注意的是，类似的机制也调节一些非上皮细胞中的铁死亡。最后，肿瘤抑制因子NF2的遗传失活（间皮瘤中常见的致瘤事件），使得恶性间皮瘤的原位小鼠模型中的癌细胞对铁死亡更敏感。这些研究结果证明了细胞间相互作用和细胞内NF2-YAP信号在决定铁蛋白死亡中的作用，并且还发现NF2-YAP信号通路中的恶性突变可以预测癌细胞对未来铁死亡诱导疗法的响应性。

铁死亡（ferroptosis）是由细胞代谢和铁依赖性脂质过氧化驱动的细胞死亡过程，与缺血性器官损伤和癌症等疾病有关。谷胱甘肽过氧化物酶4（GPX4）是一种中枢调节者，通过中和脂质过氧化物（细胞代谢的副产物）来保护细胞。直接抑制GPX4，或通过耗尽其底物谷胱甘肽或谷胱甘肽的来源（如半胱氨酸）进行间接抑制，可引发铁死亡。铁死亡有助于几种肿瘤抑制因子如p53，BAP1和延胡索酸酶的抗肿瘤功能。与预想相反的是，间充质癌细胞对铁死亡很敏感，这些细胞易于转移，并且通常对各种治疗具有抗性。

更多阅读

陈志南

陈志南，中国工程院院士，细胞生物学与生物药物专家，空军军医大学（第四军医大学）细胞生物学国家重点学科主任。长期从事炎-癌相关分子CD147系列研究，对肿瘤相关分子CD147在癌进展中的多时相、多阶段和多节点的分子调控机制的原创性研究和转化应用研究处于国际领先地位。（据中国工程院）

姜学军

姜学军，美国纪念斯隆-凯特林癌症中心姜学军实验室主任。主要研究方向：程序性细胞死亡、分子机制及其在肿瘤发生中的作用。（据美国纪念斯隆-凯特林癌症中心）

附：英文原文

Title: Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling

Author: Jiao Wu, Alexander M. Minikes, Minghui Gao, Huijie Bian, Yong Li, Brent R. Stockwell, Zhi-Nan Chen, Xuejun Jiang

Issue&Volume: Volume 572 Issue 7769

Abstract: Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated in diseases such as ischaemic organ damage and cancer. The enzyme glutathione peroxidase 4 (GPX4) is a central regulator of ferroptosis, and protects cells by neutralizing lipid peroxides, which are by-products of cellular metabolism. The direct inhibition of GPX4, or indirect inhibition by depletion of its substrate glutathione or the building blocks of glutathione (such as cysteine), can trigger ferroptosis. Ferroptosis contributes to the antitumour function of several tumour suppressors such as p53, BAP1 and fumarase. Counterintuitively, mesenchymal cancer cellswhich are prone to metastasis, and often resistant to various treatmentsare highly susceptible to ferroptosis. Here we show that ferroptosis can be regulated non-cell-autonomously by cadherin-mediated intercellular interactions. In epithelial cells, such interactions mediated by E-cadherin suppress ferroptosis by activating the intracellular NF2 (also known as merlin) and Hippo signalling pathway. Antagonizing this signalling axis allows the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis by upregulating several ferroptosis modulators, including ACSL4 and TFRC. This finding provides mechanistic insights into the observations that cancer cells with mesenchymal or metastatic property are highly sensitive to ferroptosis. Notably, a similar mechanism also modulates ferroptosis in some non-epithelial cells. Finally, genetic inactivation of the tumour suppressor NF2, a frequent tumorigenic event in mesothelioma, rendered cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma. Our results demonstrate the role of intercellular interactions and intracellular NF2YAP signalling in dictating ferroptotic death, and also suggest that malignant mutations in NF2YAP signalling could predict the responsiveness of cancer cells to future ferroptosis-inducing therapies.

DOI: 10.1038/s41586-019-1426-6

Source: https://www.nature.com/articles/s41586-019-1426-6