Autophagy and Pro-metastatic Differentiation

自噬和促转移分化

• 批准号: 10307119
• 负责人: Jayanta Debnath
• 金额: $ 33.83万
• 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 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10307119
• 关键词: Adaptor Signaling Protein; Adhesions; Aftercare; Antimalarials; Attenuated; Autophagocytosis; Autophagosome; BRCA1 gene; Behavior; Biological; Breast Cancer Model; Cancer Patient; Cells; Clinical Oncology; Complex; Cytokeratin-14 Staining Method; Cytoplasm; Data; Distant; Distant Metastasis; Epithelial; Excision; Exhibits; Gene Expression; Genes; Genetic; Genetic Induction; Homeostasis; Human; Hydroxychloroquine; Impairment; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastatic Neoplasm to the Lung; Methods; Modeling; Mus; Neoplasm Metastasis; Oncogenic; Pathway interactions; Patient-Focused Outcomes; Pattern; Pharmacology; Phenotype; Play; Primary Neoplasm; Process; Proteins; Publishing; Recurrence; Recycling; Regulation; Relapse; Residual Tumors; Role; Signal Transduction; Site; Stress; Therapeutic; Time; Tumor Expansion; Up-Regulation; base; cancer cell; cancer clinical trial; cancer recurrence; inhibition of autophagy; inhibitor; insight; interest; malignant breast neoplasm; metabolic fitness; mouse model; neoplastic cell; prevent; programs; receptor; single-cell RNA sequencing; therapy resistant; transcription factor; treatment response; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor progression

PROJECT SUMMARY Autophagy is a tightly regulated intracellular degradation and recycling process crucial for cellular homeostasis and adaptation to diverse cancer-relevant stresses. Because autophagy promotes the survival and metabolic fitness of established tumors, there is great interest in targeting autophagy to treat cancer. Importantly, anti- malarials, such as hydroxychloroquine (HCQ) are currently being repurposed as autophagy inhibitors in clinical oncology trials. However, inhibiting autophagy also results in aberrant accumulation of autophagy cargo receptors (ACRs), adaptor proteins that mediate the selective autophagic degradation of targets as well as function as multidomain signaling hubs. The accumulation of ACRs supports oncogenic progression, drives primary tumor growth and promotes therapeutic resistance in autophagy-deficient cells, but the role of ACRs during metastasis has been less clear. In recently published data, we have demonstrated that the accumulation of a specific ACR, called neighbor of BRCA1 (NBR1), promotes metastasis when autophagy is inhibited in tumor cells. In mouse mammary cancer models, genetic autophagy inhibition promotes spontaneous metastasis by enabling the outgrowth of disseminated tumor cells into overt macro-metastases. Furthermore, at both primary and metastatic sites, genetic autophagy inhibition leads to the marked expansion of tumor cells exhibiting aggressive and pro-metastatic basal epithelial differentiation, including the expression of cytokeratin 14 (CK14) and the transcription factor p63. The upregulation of NBR1 in autophagy-deficient tumors is both necessary and sufficient to promote metastatic outgrowth and pro-metastatic differentiation. Based on these findings, we hypothesize that autophagy inhibition promotes the emergence of multiple aggressive tumor subpopulations due to impaired NBR1 turnover. In aim 1, we will determine the mechanisms how NBR1 promotes basal epithelial differentiation in carcinoma cells. In aim 2, we will evaluate the effect of autophagy inhibition on tumor recurrence and intratumor heterogeneity. In aim 3, we will scrutinize how therapeutically modulating autophagy, both positively or negatively, impacts metastatic differentiation via promoting the turnover or sequestration of NBR1. Overall, this proposal will elucidate the mechanisms by which autophagy and NBR1 control aggressive differentiation programs in breast cancer and how this regulation impacts recurrence and treatment response.

项目概要 自噬是一种严格调控的细胞内降解和回收过程，对于细胞稳态至关重要 以及对各种癌症相关压力的适应。因为自噬促进生存和代谢 由于已建立的肿瘤的适应性，人们对靶向自噬来治疗癌症产生了极大的兴趣。重要的是，反 疟疾药物，如羟氯喹（HCQ）目前在临床上被重新用作自噬抑制剂 肿瘤学试验。然而，抑制自噬也会导致自噬货物的异常积累 受体（ACR）、介导靶标选择性自噬降解的衔接蛋白以及 作为多域信号枢纽。 ACR 的积累支持致癌进程，驱动 原发性肿瘤生长并促进自噬缺陷细胞的治疗抵抗，但 ACR 的作用 转移期间的情况尚不清楚。在最近发布的数据中，我们证明了累积 当肿瘤中的自噬受到抑制时，一种称为 BRCA1 邻居 (NBR1) 的特定 ACR 会促进转移 细胞。在小鼠乳腺癌模型中，基因自噬抑制通过以下方式促进自发转移： 使播散性肿瘤细胞生长成明显的宏观转移。此外，在两个小学 和转移部位，基因自噬抑制导致肿瘤细胞显着扩张 侵袭性和促转移性基底上皮分化，包括细胞角蛋白 14 (CK14) 的表达 和转录因子p63。自噬缺陷肿瘤中 NBR1 的上调既是必要的，也是必要的 足以促进转移生长和促转移分化。基于这些发现，我们 假设自噬抑制促进多种侵袭性肿瘤亚群的出现 NBR1 营业额受损。在目标 1 中，我们将确定 NBR1 促进基底上皮细胞形成的机制 癌细胞的分化。在目标2中，我们将评估自噬抑制对肿瘤复发的影响 和瘤内异质性。在目标 3 中，我们将仔细研究如何治疗性调节自噬， 通过促进 NBR1 的周转或隔离，对转移分化产生积极或消极的影响。 总体而言，该提案将阐明自噬和 NBR1 控制侵袭性的机制 乳腺癌的分化计划以及这种调节如何影响复发和治疗反应。