Targeting autophagy in the TME

项目总结/摘要 该项目的主要目标是测试缺氧肿瘤内自噬的调节 微环境（TME）可以影响循环肿瘤细胞（CTC）的存活、转移潜力和治疗效果。 反应TME是选择侵袭性肿瘤细胞的复杂滋生地，具有以下优点： 存活或转移潜力，并赋予对细胞毒性以及靶向癌症治疗的抗性。的 肿瘤转移的过程由多个步骤组成，包括肿瘤细胞从原发灶播散到转移灶。 肿瘤部位进入脉管系统或淋巴循环（内渗），循环期间存活，外渗 进入次级部位，并在靶器官部位启动和定殖。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。人们普遍认为 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， 的TME。然而，TME内自噬对促生存、转移和肿瘤生长的相对贡献， CTCs的易感性和治疗抗性表型同样是未知的。因此， 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 和耐药性。为了验证这一假设，我们提出了以下具体目标：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）研究缺氧对肿瘤细胞的影响。 在CTC中检测和监测的治疗反应中诱导自噬。

Project Summary/Abstract 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.