Examining Mitochondria Dysfunction and Oxidative Stress in Senescence

项目摘要/摘要 癌症转移占全球癌症相关死亡的90%。[1]一个被广泛接受的假说是 在癌症发展过程中，异质亚克隆群体的出现不仅推动了肿瘤的生长， 但也能使癌细胞转移到远处的器官。[2]目前的教条认为，异质性 源于癌细胞在被称为基因组的过程中持续改变其基因组的能力 然而，测序工作表明，转移瘤的遗传学通常反映了这一点。 [4-6]这表明其他机制可能驱动癌症转移，例如 染色体不稳定(CIN)。 CIN是癌症的一个特征，它是由于有丝分裂过程中染色体分离的持续错误造成的。CIN 产生包含整个染色体(数字CIN)和亚染色体的拷贝数改变 促进肿瘤异质性和加速肿瘤进化的重排(结构上的CIN)。因此，CIN是 一种强大的机制，可以快速塑造肿瘤细胞群体的表型格局。然而，无论是 CIN在癌症转移中是因果驱动因素还是仅仅是旁观者一直是人们猜测的问题 几十年。 直到最近，解决CIN在转移中的作用一直是一个实验性的技术挑战。 利用我最近通过基因操作染色体分离错误率的能力，我提议 探讨CIN在肿瘤转移中的细胞自主和非细胞自主机制。这个 拟议的博士培训工作(目标1)将调查CIN和CIN之间的基本关系 转移性癌症的行为。到目前为止，我的工作表明，除了助长核型的异质性外， CIN通过肿瘤细胞自主激活cGAS介导的胞浆DNA感应而促进肿瘤转移 途径(目标1)。[7]在接下来的两年里，我将确定靶向CIN驱动的还是CIN驱动的。 依赖途径，如cGAS-STING，可用作限制转移的治疗策略 传播和延长患者的存活期。 对于我的博士后研究(目标2)，我计划研究先天和获得性免疫细胞群体如何 在肿瘤微环境中，使用一种新的肺癌小鼠模型对CIN作出反应。在……里面 综上所述，我的研究为CIN如何在癌症的天然免疫信号中发挥作用提供了一个新的范例 转移。我的博士后研究将建立新的CIN模型，为深入了解肿瘤间质提供帮助 相互作用，并阐明潜在的治疗目标。此外，我还提出了一个全面的 培训计划，这将为我过渡到博士后研究职位做准备。

PROJECT SUMMARY/ABSTRACT Cancer metastasis is responsible for 90% of cancer-related mortality world-wide.[1] A widely-held hypothesis is that during cancer progression, heterogeneous subclonal populations emerge that not only drive tumor growth, but also enable cancer cells to metastasize to distant organs.[2] Current dogma suggests that heterogeneity stems from the ability of cancer cells to continuously alter their genome in a process known as genomic instability.[3] However, sequencing efforts have revealed that the genetics of metastases generally reflect that of the primary tumor.[4-6] This suggests that other mechanisms may drive cancer metastasis, such as chromosomal instability (CIN). CIN is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. CIN generates copy number alterations encompassing entire chromosomes (numerical CIN) and subchromosomal rearrangements (structural CIN) that promote tumor heterogeneity and accelerate tumor evolution. Thus, CIN is a powerful mechanism to rapidly shape the phenotypic landscape of tumor cell populations. However, whether CIN is a causal driver or is a mere bystander in cancer metastasis has been a matter of conjecture for decades. Until recently, addressing the role of CIN in metastasis has been an experimental technical challenge. Capitalizing on my recent ability to genetically manipulate chromosome segregation error rates, I propose to investigate the cell-autonomous and non-cell autonomous mechanisms of CIN in metastasis. The proposed doctoral training work (Aim 1) will investigate the fundamental relationship between CIN and the behavior of metastatic cancers. To date, my work revealed that in addition to fueling karyotypic heterogeneity, CIN drives metastasis through tumor-cell autonomous activation of that the cGAS-STING cytosolic DNA sensing pathway (Aim 1).[7] Over the next two years, I will determine whether targeting CIN-driven or CIN- dependent pathway such as cGAS-STING, can be used as a therapeutic strategy to limit metastatic spread and prolong patient survival. For my postdoctoral research (Aim 2), I plan to study how innate and adaptive immune cell populations within the tumor microenvironment respond to CIN using a novel mouse model of lung cancer. In summary, my research provides a novel paradigm for how CIN contributes to innate immunity signaling in cancer metastasis. My post-doctoral research will establish new models of CIN that provide insight into tumor-stromal interactions, and illuminate potential therapeutic targets. In addition, I have also proposed a comprehensive training plan that will prepare me for my transition to a post-doctoral research position.