Autophagy in Adhesion and Metastasis

描述(由申请人提供)：自噬是一个严格调控的细胞内降解和循环过程，对细胞内平衡和适应不同的癌症相关压力至关重要。在癌症中，目前的研究表明，自噬在应激状态下促进肿瘤的存活和新陈代谢的健康，并在化疗期间作为一种抵抗途径。这引起了人们对抑制自噬作为癌症治疗策略的浓厚兴趣；事实上，羟基氯喹(HCQ)等抗疟疾药物目前正在许多临床肿瘤学试验中被重新用作自噬抑制剂，这主要是因为它们在人类上的长期使用历史和良好的毒性特征。尽管有这种热情，但关于自噬抑制在癌症治疗中的长期后果，我们还有很多需要了解的。一个重要的悬而未决的问题是，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会导致转移增加，而不是减少。这些意想不到的发现提出了一种可能性，即像HCQ这样的药物自噬抑制剂可能通过促进某些癌症患者的转移而隐藏长期风险。此外，我们还获得了选择性自噬的两个介体p62/SQSTM1和NBR1的初步证据，它们指导着自噬途径如何影响乳腺癌进展和治疗反应中的转移和肿瘤细胞的增殖。基于这一初步数据，这一建议试图准确地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。我们将使用已建立的免疫功能乳腺癌模型来仔细研究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性播种和定植方面的阶段特异性效应。在目标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生长。在目标3中，我们将确定NBR1在黏附介导的信号和转移中的作用。总体而言，这些研究为自噬在转移过程中的作用提供了独特的概念性见解。

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.