Targeting autophagy in the TME

描述（由申请人提供）：该项目的主要目标是测试缺氧肿瘤微环境（TME）内自噬的调节可以影响循环肿瘤细胞（CTC）存活、转移潜力和治疗反应的想法。TME是选择具有存活或转移潜力优势的侵袭性肿瘤细胞的复杂滋生地，并赋予对细胞毒性以及靶向癌症治疗的抗性。肿瘤转移的过程由多个步骤组成，包括肿瘤细胞从原发肿瘤部位扩散到脉管系统或淋巴循环（内渗），存活 在循环过程中，外渗到次要部位，以及在靶器官部位的启动和定殖。肿瘤细胞必须成功地完成每一步，以产生临床可检测的转移性疾病。一般认为，自噬对于肿瘤细胞在营养或氧剥夺条件下的存活是必不可少的，营养或氧剥夺是TME的标志。然而，TME内的自噬对CTC的促存活、转移倾向和治疗抗性表型的相对贡献同样是未知的。因此，有一个很好的机会来解开这种生物学，并阐明更好的治疗设计以及治疗监测。我们假设TME内缺氧诱导的自噬有助于CTC存活、肿瘤转移和化疗耐药性。为了检验这一假设，我们提出了以下具体目的：1）确定缺氧调节的自噬在异种移植小鼠模型中肿瘤生长和转移中的重要性; 2）评估异种移植肿瘤和CTC中的自噬和凋亡; 3）研究缺氧诱导的自噬对CTC中检测和监测的治疗反应的影响。 公共卫生相关性：这项研究的成功实施不仅将更好地了解TME内缺氧诱导的自噬在肿瘤细胞存活，转移潜力和治疗抗性方面的生物学功能，而且还将有助于开发一种宝贵的工具来监测CTC中的分子事件和生物标志物，以指导癌症的诊断，预后和治疗。

DESCRIPTION (provided by applicant): The major goal of this project is to test the idea that modulation of autophagy within the hypoxic tumor microenvironment (TME) can impact circulating tumor cell (CTC) survival, metastatic potential, and therapeutic response. The TME is a complex breeding ground for selection of aggressive tumor cells with an advantage of survival or metastatic potential and confers resistance to cytotoxic as well as targeted cancer therapy. The process of tumor metastasis consists of multiple steps, including tumor cell dissemination from the primary tumor site into the vasculature or lymphatic circulation (intravasation), survival during circulation, extravasation into the secondary site, and initiation and colonization at the target organ site. Tumor cells must successfully complete each step to give rise to clinically detectable metastatic disease. It is generally accepted that autophagy is essential for tumor cell survival under conditions of nutrient or oxygen deprivation, the hallmarks of the TME. However, the relative contribution of autophagy within the TME to the pro-survival, metastasis- prone, and therapy-resistant phenotypes of CTCs is similarly unknown. There is therefore a great opportunity to unravel this biology and shed light on better therapeutic designs as well as therapy monitoring. We hypothesize that hypoxia-induced autophagy within the TME contributes to CTC survival, tumor metastasis, and chemoresistance. To test this hypothesis, we propose the following Specific Aims: 1) To determine the importance of hypoxia-regulated autophagy in tumor growth and metastasis in xenograft mouse models; 2) To evaluate autophagy and apoptosis in xenograft tumors and CTCs; 3) To investigate the effect of hypoxia- induced autophagy on therapeutic response as detected and monitored in CTCs. PUBLIC HEALTH RELEVANCE: Successful implementation of this research will not only offer a better understanding of the biological functions of hypoxia-induced autophagy within the TME in tumor cell survival, metastatic potential, and therapeutic resistance, but will also aid in the effort to develop an invaluable tool to monitor molecular events and biomarkers in CTCs for guiding diagnosis, prognosis and treatment of cancer.