Autophagy in Adhesion and 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再循环过程，对于细胞稳态和适应不同的癌症相关应激至关重要。在癌症中，目前的研究表明，自噬在应激期间促进肿瘤的存活和代谢适应性，并在化疗期间作为抵抗途径。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，抗疟疾药如羟氯喹（HCQ）目前在许多临床肿瘤学试验中被重新用作自噬抑制剂，这主要是由于它们在人类中的长期使用历史和良好的毒性特征。尽管有这种热情，我们仍然需要了解自噬抑制在癌症治疗中的长期后果。一个重要的未回答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功能尚未在体内进行严格的测试，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这样的药理学自噬抑制剂可能通过增强某些癌症患者的转移而具有长期风险。此外，我们已经获得了初步的证据表明，选择性自噬的两种介质，p62/SQSTM 1和NBR 1，指导自噬途径如何影响乳腺癌进展和治疗反应期间的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。我们将采用已建立的免疫活性乳腺癌模型来详细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性播种和定殖中的阶段特异性作用。在目标2中，我们将确定自噬缺陷细胞中p62/SQSTM 1积累如何影响转移性生长。在目标3中，我们将确定NBR 1在粘附介导的信号传导和转移中的作用。总的来说，这些研究为转移过程中自噬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.