Autophagy in Adhesion and Metastasis

粘附和转移中的自噬

• 批准号: 9004606
• 负责人: Jayanta Debnath
• 金额: $ 31.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9004606
• 关键词: Ablation; Adhesions; Affect; Anoikis; Antimalarials; Attenuated; Autophagocytosis; Breast Cancer Model; Breast cancer metastasis; Cancer Etiology; Cancer Patient; Cell Adhesion; Cell Proliferation; Cells; Clinical Oncology; Complex; Data; Extravasation; Focal Adhesions; Genetic; Health; Homeostasis; Human; Hydroxychloroquine; Immune; Laboratories; Learning; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mediator of activation protein; Metabolic; Modeling; Mus; Neoplasm Metastasis; Oncogenes; Pathway interactions; Phenotype; Process; Publishing; RNA Interference; Recording of previous events; Recycling; Regulation; Research; Resistance; Risk; Role; Scaffolding Protein; Signal Transduction; Site; Staging; Stress; Testing; Therapeutic; Toxic effect; Tumor Suppressor Proteins; base; cancer therapy; chemotherapy; epithelial to mesenchymal transition; fitness; in vivo; inhibition of autophagy; inhibitor/antagonist; insight; interest; mortality; neoplastic cell; response; stressor; tumor; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Autophagy is a tightly regulated intracellular degradation and recycling process that is crucial for cellular homeostasis and adaptation to diverse cancer-relevant stresses. In cancer, current research suggests that autophagy promotes the survival and metabolic fitness of tumors during stress and serves as a resistance pathway during chemotherapy. This has generated significant interest in autophagy inhibition as a therapeutic strategy in cancer; indeed, anti-malarials such as hydroxychloroquine (HCQ) are currently being repurposed as autophagy inhibitors in numerous clinical oncology trials, largely due to their long history of use in humans and well-established toxicity profiles. Despite this enthusiasm, we have much to learn about the long-term consequences of autophagy inhibition in cancer therapy. An important unanswered question is how autophagy impacts metastasis, a principal cause of cancer mortality. The functions of autophagy during metastasis have not been rigorously tested in vivo and our preliminary studies in mouse mammary cancer models indicate that autophagy inhibition in tumor cells results in increased, not decreased, metastasis. These unexpected findings raise the possibility that pharmacological autophagy inhibitors like HCQ may harbor long-term risks by enhancing metastasis in certain cancer patients. In addition, we have obtained preliminary evidence that two mediators of selective autophagy, p62/SQSTM1 and NBR1, direct how the autophagy pathway influences metastasis and tumor cell proliferation during mammary cancer progression and response to therapy. Based on this preliminary data, this proposal seeks to precisely define the stage at which autophagy suppresses mammary cancer metastasis in vivo and to dissect the mechanisms by which autophagy deficiency promotes the metastatic phenotype. We will employ established immmunocompetent mammary cancer models to scrutinize the functions of the autophagy pathway during metastatic progression in vivo. In Aim 1, we will determine the stage-specific effects of autophagy in suppressing metastatic seeding and colonization. In Aim 2, we will determine how p62/SQSTM1 accumulation in autophagy deficient cells impacts metastatic outgrowth. In Aim 3, we will determine the role of NBR1 in adhesion-mediated signaling and metastasis. Overall, these studies provide unique conceptual insight into the role of autophagy during metastasis.

描述（由申请人提供）：自噬是一种严格调控的细胞内降解和回收过程，对于细胞稳态和适应多种癌症相关应激至关重要。在癌症中，目前的研究表明，自噬可促进肿瘤在应激期间的存活和代谢适应性，并在化疗期间充当耐​​药途径。这引起了人们对自噬抑制作为癌症治疗策略的极大兴趣。事实上，羟氯喹 (HCQ) 等抗疟疾药物目前在众多临床肿瘤学试验中被重新用作自噬抑制剂，这主要是由于它们在人类中的长期使用历史和明确的毒性特征。尽管有这样的热情，但关于自噬抑制在癌症治疗中的长期后果，我们还有很多东西需要了解。一个尚未解答的重要问题是自噬如何影响转移，这是癌症死亡的主要原因。转移过程中自噬的功能尚未经过严格的体内测试，我们在小鼠乳腺癌模型中的初步研究表明，肿瘤细胞中的自噬抑制会导致转移增加，而不是减少。这些意外的发现提出了一种可能性，即 HCQ 等药物自噬抑制剂可能会通过增强某些癌症患者的转移而带来长期风险。此外，我们还获得了初步证据，表明选择性自噬的两种介质p62/SQSTM1和NBR1在乳腺癌进展和治疗反应过程中指导自噬途径如何影响转移和肿瘤细胞增殖。基于这些初步数据，该提案旨在精确定义自噬抑制体内乳腺癌转移的阶段，并剖析自噬缺陷促进转移表型的机制。我们将利用已建立的免疫功能正常的乳腺癌模型来检查体内转移进展过程中自噬途径的功能。在目标 1 中，我们将确定自噬在抑制转移播种和定植方面的特定阶段效应。在目标 2 中，我们将确定自噬缺陷细胞中 p62/SQSTM1 的积累如何影响转移生长。在目标 3 中，我们将确定 NBR1 在粘附介导的信号传导和转移中的作用。总的来说，这些研究为自噬在转移过程中的作用提供了独特的概念见解。