Novel roles of endosome-mediated receptor recycling during brain metastatic outgrowth

内体介导的受体再循环在脑转移生长过程中的新作用

• 批准号: 9192374
• 负责人: Erin Nicole Howe
• 金额: $ 5.8万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192374
• 关键词: Accounting; Bicuculline; Blood - brain barrier anatomy; Blood Circulation; Brain; Breast Cancer Cell; Breast Cancer Prevention; Characteristics; Clinical; Clinical Management; Clinical Trials; Coculture Techniques; Communication; Development; ERBB2 gene; Endosomes; Environment; GABA Receptor; Genetic; Human; Incidence; Investigation; Lesion; Localized Disease; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Metastatic malignant neoplasm to brain; Methodology; Nature; Neoplasm Metastasis; Neuroglia; Neurologic; Neurotransmitters; Pathway interactions; Patients; Pharmaceutical Preparations; Primary Neoplasm; Process; RNA Interference; RNA interference screen; Recycling; Relapse; Repression; Research; Role; Signal Pathway; Signal Transduction; Specificity; Systemic disease; Translations; Trastuzumab; Up-Regulation; Woman; cancer cell; cancer diagnosis; chemotherapy; clinical efficacy; combinatorial; gamma-Aminobutyric Acid; lapatinib; malignant breast neoplasm; metastatic process; mortality; neoplastic cell; nervous system disorder; non-genetic; novel; novel therapeutics; patient population; pre-clinical; preclinical efficacy; prevent; receptor; receptor recycling; research study; screening; success; targeted treatment; trait; transcriptome sequencing; tumor growth

Project Summary Breast cancer remains the most commonly diagnosed cancer for women, and 30% of mortality is attributable to the spread of cancer to the brain in a process called metastasis. When brain metastases are present, women have a five-year survival of only 25%, with a median survival of less than one year. Unfortunately, as new treatments provide better control of primary breast cancer, the incidence of brain metastases is increasing. The greatest challenge in the clinical management of patients who relapse with brain metastasis is the extremely limited treatment options. Systemic treatments, such as chemotherapies or targeted therapies, cannot effectively treat micrometastatic brain lesions or prevent brain relapse, largely due to their inability to penetrate the blood-brain barrier. Currently, no clinically approved drug shows promising efficacy for brain metastases. Therefore, it is urgent that we expand our mechanistic understanding of breast cancer brain metastases so that we can develop new and effective systemic targeted therapeutics for this rapidly expanding patient population. Although thousands of cancer cells can be found in the circulation of patients, the formation of brain metastases is an inefficient and highly selective process. This is due in part to the unique nature of the brain microenvironment, which includes expression of neurotransmitters not found elsewhere in the body. One neurotransmitter pathway, the GABA signaling pathway, is increased in clinical breast cancer brain metastases. Mutual communication between cancer cells and the metastatic environment is essential for the successful formation of metastases. The cellular characteristics of the tumor cell – both its inherent genetic traits as well as yet to be defined secondary, non-genetic changes influenced by the microenvironment – dictate its ability to successfully complete the metastatic process. This proposal investigates a novel mechanism of breast cancer adaptation to the brain microenvironment, and seeks to identify how this adaptation subsequently propels metastatic outgrowth. A high throughput experimental methodology employing RNA-seq and RNAi functional screening identified putative mediators of brain metastasis. Rab11, a component of the endosomal recycling pathway, is up-regulated during adaptation to the brain microenvironment, suggesting involvement of recycling in brain metastasis. As Rab11 regulates the specificity of vesicular cargo during endosomal recycling, this proposal hypothesizes that Rab11 mediates breast cancer brain metastatic outgrowth through recycling mediated up-regulation of the GABA receptor. The proposed research will 1) determine the mechanism and consequence of Rab11 up-regulation in brain metastasis; 2) explore the mechanism of Rab11-mediated GABA receptor recycling; 3) investigate the efficacy of targeting the recycling pathway in the treatment of brain metastases.

项目概要 乳腺癌仍然是女性最常见的癌症，死亡率高达 30% 归因于癌症在称为转移的过程中扩散到大脑。当发生脑转移时 目前，女性的五年生存率仅为25%，中位生存期不足一年。 不幸的是，随着新的治疗方法可以更好地控制原发性乳腺癌，脑癌的发病率 转移正在增加。脑复发患者临床治疗的最大挑战 转移是极其有限的治疗选择。全身治疗，例如化疗或 靶向治疗不能有效治疗脑部微转移病灶或预防脑部复发，很大程度上是由于 他们无法穿透血脑屏障。目前尚无临床批准的药物显示出有希望的 对脑转移瘤有疗效。因此，迫切需要扩大对乳房机制的认识。 癌症脑转移，以便我们能够为此开发新的有效的系统靶向治疗方法 患者群体迅速扩大。 尽管在患者的循环中可以发现数以千计的癌细胞，但大脑的形成 转移是一个低效且高度选择性的过程。这部分是由于大脑的独特性质 微环境，其中包括身体其他地方未发现的神经递质的表达。一 神经递质通路（GABA 信号通路）在临床乳腺癌脑中增加 转移。癌细胞与转移环境之间的相互沟通对于转移至关重要。 成功形成转移。肿瘤细胞的细胞特征——其固有的遗传 性状以及尚未定义的受微环境影响的次要、非遗传变化 - 决定其成功完成转移过程的能力。该提案调查了一部小说 乳腺癌适应大脑微环境的机制，并试图确定这是如何 适应随后推动转移生长。高通量实验方法 采用 RNA-seq 和 RNAi 功能筛选确定了脑转移的假定介质。拉布11 内体循环途径的组成部分，在适应大脑过程中上调 微环境，表明循环参与脑转移。由于 Rab11 调节特异性 内体回收过程中囊泡货物的含量，该提议假设 Rab11 介导乳腺癌 通过再循环介导的 GABA 受体上调来促进脑转移。拟议的 研究将1）确定Rab11上调在脑转移中的机制和后果； 2） 探讨Rab11介导的GABA受体回收机制； 3）研究靶向效果 脑转移治疗中的回收途径。