Autophagy Heterogeneity and Tumor Metastasis

自噬异质性与肿瘤转移

• 批准号: 10212775
• 负责人: HONG-GANG WANG
• 金额: $ 41.7万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212775
• 关键词: Affect; Autophagocytosis; Breast Cancer Cell; Breast Cancer Model; Breast cancer metastasis; Cancer Cell Growth; Cell Communication; Cell Survival; Cells; Cessation of life; Chloroquine; Clinical Trials; Collaborations; Communication; Complex; Coupling; Cytomegalovirus; Degradation Pathway; Dominant-Negative Mutation; Fatty acid glycerol esters; Fibronectins; Gene Expression Profiling; Goals; Growth; Heterogeneity; Homeostasis; Hydroxychloroquine; Hypoxia; Integrins; Knowledge; Label; MDA MB 231; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolic; Metastatic Neoplasm to the Lung; Monitor; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Nutrient; Organelles; Outcome; Oxygen; Phenotype; Phosphotransferases; Physiological; Primary Neoplasm; Prognosis; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Recycling; Response Elements; Role; Signal Transduction; Stress; System; Testing; Therapeutic; Tumor Promoters; Tumor Suppressor Proteins; Xenograft procedure; base; cancer cell; cancer survival; cancer therapy; chemotherapy; epithelial to mesenchymal transition; improved; in vivo; inhibitor/antagonist; insight; mammary; mechanotransduction; mitochondrial metabolism; mouse model; mutant; neoplastic cell; novel; nutrient deprivation; patient response; promoter; response; targeted cancer therapy; transcriptome; tumor; tumor growth; tumor heterogeneity; tumor hypoxia; tumor microenvironment; tumor progression; vector

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.

本项目的目的是研究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， 环境或细胞内应激，用于受损蛋白质或细胞器的再循环， 细胞内稳态虽然自噬作为肿瘤抑制因子限制恶性转化， 使癌细胞能够在营养和氧气缺乏的肿瘤微环境中生长和存活 （TME）。缺氧与增强的转移和不良预后相关;然而，缺氧的作用- 诱导的自噬在肿瘤进展中的作用尚不清楚。我们建立了一种新颖的原位乳房模型 在缺氧肿瘤区域自噬被生理性和可逆性抑制的癌症。特别是 缺氧肿瘤区域自噬的丧失显著增加肺转移而不影响原发性 肿瘤生长此外，缺氧诱导的自噬的丧失也增强了肺转移， 自噬被组成性抑制的肿瘤。总的来说，我们假设缺氧的丧失- 诱导的自噬通过与附近的自噬协作增加肿瘤应激以促进转移， 有能力的细胞建立具有高和低自噬活性的肿瘤亚群， 通过纤连蛋白-整合素信号传导和代谢偶联。假设将在两个特定的 目的：1）鉴定和表征在化疗期间具有增加的转移潜能的肿瘤亚群。 缺氧诱导的自噬丧失或诱导自噬异质性; 2）探讨缺氧诱导自噬的机制 异质性自噬活性通过其介导肿瘤内细胞通讯。完成这些 这些研究将显著增强我们对肿瘤转移中自噬的理解，并提供对 适当调节自噬以治疗癌症。