Autophagy Heterogeneity and Tumor Metastasis

这个项目的目标是调查乳腺癌中自噬活性的瘤内异质性。 转移。自噬是一种高度保守的溶酶体降解途径，它是由 环境或细胞内压力，以回收受损的蛋白质或细胞器并维持 细胞动态平衡。虽然自噬是一种肿瘤抑制因子，可以限制恶性转化，但它也 使癌细胞在缺乏营养和氧气的肿瘤微环境中生长和存活 (TME)。缺氧与转移增强和预后不良有关；然而，缺氧的作用- 诱导自噬在肿瘤进展中的作用尚不清楚。我们建立了一种新的乳房原位模型 在缺氧性肿瘤区域，自噬受到生理性和可逆性抑制的癌症。值得注意的是， 缺氧肿瘤区域自噬丧失显著增加肺转移而不影响原发肿瘤 肿瘤生长。此外，与低氧诱导的自噬丧失相比，低氧诱导的自噬的丧失也增强了肺转移。 自噬受到结构性抑制的肿瘤。总而言之，我们假设缺氧的消失- 诱导的自噬增加了肿瘤的压力，通过与附近的自噬合作促进转移- 有能力的细胞建立具有高和低自噬活性的肿瘤亚群来驱动转移 通过纤维连接蛋白-整合素信号转导和代谢偶联。这些假设将在两个具体的方面进行检验 目的：1)确定和描述在治疗过程中转移潜能增加的肿瘤亚群 缺氧诱导的自噬缺失或自噬异质性的诱导；2)探讨其机制 异质自噬活性通过其介导肿瘤内细胞间的通讯。完成这些工作 研究将显著增强我们对自噬在肿瘤转移中的理解，并提供对 自噬的适当调节用于癌症治疗。

The goal of this project is to investigate the intratumoral heterogeneity of autophagy activity in breast cancer metastasis. Autophagy is a highly conserved lysosomal degradation pathway that is induced in response to environmental or intracellular stress for the recycling of damaged proteins or organelles and the maintenance of cellular homeostasis. While autophagy serves as a tumor suppressor to limit malignant transformation, it also enables the growth and survival of cancer cells within the nutrient- and oxygen-deprived tumor microenvironment (TME). Hypoxia is associated with enhanced metastasis and poor prognosis; however, the role of hypoxia- induced autophagy in tumor progression is not clear. We have established a novel orthotopic model of breast cancer in which autophagy is physiologically and reversibly suppressed in hypoxic tumor regions. Notably, the loss of autophagy in hypoxic tumor regions significantly increases lung metastasis without affecting primary tumor growth. Moreover, the loss of hypoxia-induced autophagy also enhances lung metastasis compared to tumors in which autophagy is constitutively suppressed. Collectively, we hypothesize that the loss of hypoxia- induced autophagy increases tumor stress to promote metastasis via collaboration with nearby autophagy- competent cells to establish tumor subpopulations with high and low autophagic activity that drive metastasis through the fibronectin-integrin signaling and metabolic coupling. The hypotheses will be tested in two Specific Aims: 1) To identify and characterize the tumor subpopulations with increased metastatic potential during the loss of hypoxia-induced autophagy or induction of autophagy heterogeneity; 2) To investigate the mechanisms by which heterogeneous autophagy activity mediates intra-tumor cell communication. Completion of these studies will significantly enhance our understanding of autophagy in tumor metastasis and provide insight into the appropriate modulation of autophagy for cancer therapy.