Autophagy in Adhesion and Metastasis

描述（由申请人提供）：自噬是一种受到严格调控的细胞内降解和再循环过程，对细胞稳态和适应各种癌症相关应激至关重要。在癌症中，目前的研究表明，自噬促进肿瘤在应激下的生存和代谢适应性，并在化疗期间作为耐药途径。这引起了对自噬抑制作为癌症治疗策略的极大兴趣；事实上，抗疟疾药物，如羟氯喹（HCQ），目前在许多临床肿瘤试验中被重新用作自噬抑制剂，主要是因为它们在人类中的使用历史悠久，并且具有明确的毒性。尽管有这种热情，我们对自噬抑制在癌症治疗中的长期后果还有很多要了解。一个重要的未解决的问题是自噬如何影响转移，转移是癌症死亡的主要原因。自噬在转移过程中的作用尚未在体内得到严格的测试，我们在小鼠乳腺癌模型中的初步研究表明，抑制肿瘤细胞的自噬导致肿瘤细胞的转移增加，而不是减少。这些意想不到的发现提出了一种可能性，即药物自噬抑制剂如HCQ可能通过增强某些癌症患者的转移而具有长期风险。此外，我们已经获得了两种选择性自噬介质p62/SQSTM1和NBR1的初步证据，指导自噬途径如何影响乳腺癌进展过程中肿瘤细胞的转移和增殖以及对治疗的反应。基于这些初步数据，本研究旨在精确定义体内自噬抑制乳腺癌转移的阶段，并剖析自噬缺陷促进转移表型的机制。我们将采用已建立的具有免疫能力的乳腺癌模型来研究自噬途径在体内转移过程中的功能。在目的1中，我们将确定自噬在抑制转移播种和定植方面的阶段特异性作用。在Aim 2中，我们将确定p62/SQSTM1在自噬缺陷细胞中的积累如何影响转移性生长。在Aim 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。

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.