Autophagy and Pro-metastatic Differentiation

自噬和促转移分化

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要自噬是严格调节的细胞内降解和回收过程，对细胞稳态至关重要并适应了与癌症相关的多种应力。因为自噬促进了生存和代谢既定肿瘤的适应性，对靶向自噬治疗癌症引起了极大的兴趣。重要的是，反疟疾，例如羟氯喹（HCQ），目前正在重新使用为临床中的自噬抑制剂肿瘤学试验。但是，抑制自噬也会导致自噬货物的异常积累受体（ACR），介导靶标的选择性自噬降解的衔接蛋白以及充当多域信号集线器。 ACR的积累支持致癌进展，驱动器原发性肿瘤生长并促进自噬缺陷细胞中的治疗性抗性，但ACR的作用在转移期间还不清楚。在最近发布的数据中，我们证明了积累当自噬在肿瘤中抑制自噬时，称为BRCA1（NBR1）的特定ACR促进转移细胞。在小鼠乳腺癌模型中，遗传自噬抑制促进了自发转移使散布的肿瘤细胞的生长能够生长到明显的宏观过程中。此外，在两个主要和转移性位点，遗传自噬抑制导致表现出明显的肿瘤细胞膨胀侵略性和促偏基底上皮分化，包括细胞角蛋白14的表达（CK14）和转录因子p63。自噬缺陷肿瘤中NBR1的上调既需要足以促进转移性的产物和促态分化。基于这些发现，我们假设自噬抑制促进了多个侵袭性肿瘤亚群的出现损害NBR1的营业额。在AIM 1中，我们将确定NBR1如何促进基础上皮的机制癌细胞的分化。在AIM 2中，我们将评估自噬抑制对肿瘤复发的影响和肿瘤内异质性。在AIM 3中，我们将仔细检查治疗方式如何调节自噬，两者都积极或负面的，通过促进NBR1的周转或隔离来影响转移性分化。总体而言，该提案将阐明自噬和NBR1控制侵略性的机制乳腺癌的分化计划以及该调节如何影响复发和治疗反应。