Dissecting the role of Hippo signaling in platinum-based chemotherapy

项目总结 以铂为基础的化疗已被广泛用于治疗包括乳腺在内的各种实体肿瘤， 肺癌和卵巢癌。最初的治疗成功是通过以铂为基础的化疗药物，如 然而，一些肿瘤被发现对顺铂具有内在耐药性或逐渐产生耐药性。 顺铂治疗。这种耐药性极大地限制了它们的治疗潜力。值得注意的是，以铂为基础的 化合物是唯一应用于癌症治疗的含有重金属的化疗药物，这会导致 独特的机制解释了他们的抵抗。其中，细胞防御机制，它 隔离、储存、运输和排出重金属，是这种以铂为基础的药物的支柱。 抵抗。因此，阐明重金属反应的调控不仅有助于识别关键因素 这导致了人类癌症对顺铂的耐药性，但也开发了化疗增敏方法 顺铂耐药癌症患者的治疗。 来自多个模型系统的研究已经完全确立了河马通路是一条关键的信号通路， 通过限制细胞增殖和刺激细胞凋亡来控制器官和组织的大小。河马小路 可以感知生长条件，并通过调节其下游效应物YAP/TAZ来控制细胞增殖。 值得注意的是，河马途径的解除调控与人类癌症中顺铂的耐药有关， 而其潜在的机制尚不完全清楚。有趣的是，我们的初步研究显示，河马 信号缺陷可以促进基因的转录，这些基因能够增加重金属外流和 中和，导致癌细胞对顺铂等铂类化疗药物产生抗药性。在这 项目中，我们将阐明河马通路调节的重金属动态平衡在驱动顺铂中的作用 并检测河马通路是否可作为顺铂的化疗增敏剂。 AIM 2的相关化疗。

PROJECT SUMMARY The platinum-based chemotherapy has been widely used for treating a variety of solid tumors including breast, lung and ovarian cancers. Initial therapeutic success is achieved by the platinum-based chemo-drugs like cisplatin; however, a number of tumors are found to be intrinsically resistant or gradually develop resistance to cisplatin treatment. This resistance greatly limits their therapeutic potential. Notably, the platinum-based compounds are the only heavy metal containing chemo-drugs applied to cancer treatment, which results in unique mechanisms accounting for their resistance. Of them, the cellular defensive machinery, which sequesters, stores, transports and expels heavy metals, represents a mainstay of such platinum-based drug resistance. Therefore, elucidating the regulation of heavy metal response will help not only identify key players that drives cisplatin resistance in human cancers, but also develop chemo-sensitizing approaches for the treatment of patients suffered from the cisplatin-resistant cancers. Studies from multiple model systems have fully established the Hippo pathway as a key signaling pathway that controls organ and tissue size via restricting cell proliferation and stimulating cell apoptosis. The Hippo pathway can sense growth conditions and control cell proliferation by modulating its downstream effectors YAP/TAZ. Notably, deregulation of the Hippo pathway has been connected with cisplatin resistance in human cancers, while the underlying mechanism is not fully understood. Interestingly, our preliminary studies revealed that Hippo signaling deficiency can promote the transcription of genes that are able to increase heavy metal efflux and neutralization, resulting in the cancer cell resistance to the platinum-based chemo-drugs like cisplatin. In this project, we will elucidate the role of the Hippo pathway-regulated heavy metal homeostasis in driving cisplatin resistance in Aim 1, and test whether the Hippo pathway can be employed as a chemo-sensitizer for the cisplatin- related chemotherapy in Aim 2.