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

项目摘要 乳腺癌仍然是女性最常见的确诊癌症，30%的死亡率是 可归因于癌症在一个称为转移的过程中扩散到大脑。当脑转移瘤 目前，女性的五年存活率只有25%，中位数存活率不到一年。 不幸的是，随着新的治疗方法更好地控制了原发性乳腺癌，脑部疾病的发病率 转移性肿瘤正在增加。脑部复发患者临床管理面临的最大挑战 转移是极其有限的治疗选择。全身治疗，如化疗或 靶向治疗不能有效地治疗脑微转移病变或防止脑复发，主要原因是 他们无法穿透血脑屏障。目前，没有临床批准的药物显示前景光明。 对脑转移瘤的疗效。因此，当务之急是扩大我们对乳房的机械性理解 因此，我们可以开发新的、有效的系统性靶向治疗方法 迅速扩大的病人人数。 虽然在患者的血液循环中可以发现数以千计的癌细胞，但脑部的形成 转移是一个低效和高度选择性的过程。这在一定程度上是由于大脑的独特性质。 微环境，包括身体其他部位没有的神经递质的表达。一 临床乳腺癌脑内GABA信号通路--神经递质通路增加 转移瘤。癌细胞和转移环境之间的相互沟通对于 成功形成转移灶。肿瘤细胞的细胞特征--既有其固有的基因 特征以及尚未定义的受微环境影响的次要、非遗传变化- 决定了它成功完成转移过程的能力。这份提案调查的是一部小说 乳腺癌对脑微环境的适应机制，并试图确定这一机制 适应随后会推动转移性外生。一种高通量的实验方法 使用RNA-seq和RNAi功能筛选确定了脑转移的假定介质。Rab11，a 内体循环途径的组成部分，在适应大脑的过程中上调 微环境，提示循环参与脑转移。AS Rab11调节特异性 在内体循环过程中的囊泡物质，这一建议假设Rab11参与乳腺癌的发生 脑转移性生长通过循环介导GABA受体的上调。建议数 研究将1)确定Rab11在脑转移中上调的机制和后果；2) 探讨Rab11介导的GABA受体再循环的机制；3)研究靶向效应 脑转移瘤治疗中的循环途径。

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.