Targeting autophagy in the TME

描述(由申请人提供)：本项目的主要目标是测试低氧肿瘤微环境(TME)中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是选择具有生存或转移潜力的侵袭性肿瘤细胞的复杂温床，并对细胞毒和靶向癌症治疗具有抵抗力。肿瘤的转移过程包括多个步骤，包括肿瘤细胞从原发肿瘤部位扩散到血管或淋巴循环(血管内)、生存 在循环过程中，渗入次级部位，并在靶器官部位启动和定植。肿瘤细胞必须成功地完成每一步，才能产生临床上可检测到的转移性疾病。人们普遍认为，在营养或缺氧条件下，自噬对于肿瘤细胞的生存是必不可少的，这是TME的特征。然而，TME内的自噬对CTCs的亲生存、易转移和治疗耐药表型的相对贡献同样未知。因此，有一个很好的机会来揭示这一生物学，并阐明更好的治疗设计以及治疗监测。我们假设低氧诱导的TME中的自噬有助于CTC存活、肿瘤转移和化疗耐药。为了验证这一假设，我们提出了以下具体目标：1)确定低氧调节的自噬在异种移植瘤小鼠模型中的肿瘤生长和转移中的重要性；2)评估异种移植瘤和CTCs中的自噬和凋亡；3)研究在CTCs中检测和监测的低氧诱导自噬对治疗反应的影响。 公共卫生相关性：这项研究的成功实施不仅将使我们更好地了解TME内缺氧诱导的自噬在肿瘤细胞存活、转移潜能和治疗耐药中的生物学功能，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记物，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.