Autophagy and Pro-metastatic Differentiation

项目总结 自噬是一种严格调控的细胞内降解和循环过程，对细胞内平衡至关重要。 以及适应不同的癌症相关压力。因为自噬促进了生存和新陈代谢 对于已建立的肿瘤的适应性，靶向自噬治疗癌症有很大的兴趣。重要的是，反- 疟疾药物，如羟基氯喹(Hcq)，目前正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(ACRs)，介导靶标选择性自噬降解的接头蛋白以及 充当多域信令集线器。ACRs的积累支持致癌进展，驱动 原发肿瘤生长并促进自噬缺陷细胞的治疗耐药性，但ACRs的作用 转移的过程还不太清楚。在最近公布的数据中，我们已经证明了 一种称为BRCA1邻居(NBR1)的特定ACR，当肿瘤自噬被抑制时，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 使扩散的肿瘤细胞生长成为明显的大转移。此外，在两个初选阶段 和转移部位，基因自噬抑制导致肿瘤细胞显著扩张，表现为 侵袭性和转移性基底上皮分化，包括细胞角蛋白14(CK14)的表达 以及转录因子p63。NBR1在自噬缺陷肿瘤中的上调既是必要的，也是 足以促进转移性生长和转移性分化。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 与NBR1周转受损有关。在目标1中，我们将确定NBR1如何促进基底上皮细胞 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地调节自噬，两者 无论是积极的还是消极的，都通过促进NBR1的周转或隔离来影响转移分化。 总体而言，这项提议将阐明自噬和NBR1控制攻击性的机制 乳腺癌的分化计划以及这一调控如何影响复发和治疗反应。

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.