Examining Mitochondria Dysfunction and Oxidative Stress in Senescence

项目概要/摘要 癌症转移是全世界90%的癌症相关死亡率的原因。[1]一个被广泛接受的假设是， 在癌症进展过程中，异质亚克隆群体的出现不仅驱动肿瘤生长， 还能使癌细胞转移到远处器官。[2]目前的教条认为异质性 癌细胞在一个称为基因组的过程中不断改变其基因组的能力， 不稳定[3]然而，测序工作已经揭示，转移瘤的遗传学通常反映出， 原发性肿瘤[4-6]这表明其他机制可能会驱动癌症转移，例如 染色体不稳定性（CIN）。 CIN是由有丝分裂期间染色体分离的持续错误引起的癌症的标志。CIN 产生涵盖整个染色体的拷贝数改变（数值CIN）和亚染色体的拷贝数改变。 结构性CIN是一种促进肿瘤异质性和加速肿瘤演变的基因重排（结构性CIN）。因此，CIN 一种快速塑造肿瘤细胞群体表型景观的强大机制。但无论 CIN在癌症转移中是一个因果驱动因素还是仅仅是一个旁观者， 几十年 直到最近，解决CIN在转移中的作用一直是一个实验技术挑战。 利用我最近在基因上操纵染色体分离错误率的能力，我建议 探讨CIN转移的细胞自主性和非细胞自主性机制。的 拟议的博士生培养工作（目标1）将调查CIN和 转移性癌症的行为。到目前为止，我的工作表明，除了助长核型异质性， CIN通过cGAS-STING细胞溶质DNA传感的肿瘤细胞自主激活来驱动转移 途径（目标1）。[7]在接下来的两年里，我将决定是针对CIN驱动还是CIN- 依赖性途径，如cGAS-STING，可用作限制转移性肿瘤的治疗策略。 传播并延长患者存活时间。 对于我的博士后研究（目标2），我计划研究先天性和适应性免疫细胞群 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 总之，我的研究提供了一个新的范例，CIN如何有助于先天免疫信号在癌症 转移我的博士后研究将建立新的CIN模型，提供对肿瘤间质 相互作用，并阐明潜在的治疗靶点。此外，我还提出了一个全面的 这份培训计划将为我向博士后研究职位的过渡做好准备。

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.