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诊断的癌症，30%的死亡率是由乳腺癌引起的。 这是由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，妇女的五年生存率只有25%，中位生存期不到一年。 不幸的是，随着新的治疗方法对原发性乳腺癌提供了更好的控制， 转移正在增加。脑卒中复发患者临床管理的最大挑战 转移是极其有限的治疗选择。全身治疗，如化疗或 靶向治疗不能有效治疗微转移性脑病变或预防脑复发，主要是由于 无法穿透血脑屏障目前，没有临床批准的药物显示有希望 脑转移的疗效。因此，我们迫切需要扩大我们对乳房的机械理解 癌症脑转移，这样我们就可以开发新的和有效的全身靶向治疗方法， 患者群体迅速扩大。 虽然在患者的血液循环中可以发现成千上万的癌细胞，但脑组织的形成 转移是一个效率低下和高度选择性的过程。这部分是由于大脑的独特性质 微环境，其中包括在身体其他地方没有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 转移癌细胞和转移环境之间的相互交流对于肿瘤的转移是至关重要的。 成功形成转移。肿瘤细胞的细胞特征-其固有的遗传 性状以及尚未被定义的次要的，受微环境影响的非遗传变化- 决定了其成功完成转移过程的能力。这个提议调查了一部小说 乳腺癌适应大脑微环境的机制，并试图确定这是如何发生的。 适应随后推动转移性生长。一种高通量实验方法 使用RNA-seq和RNAi功能筛选鉴定了脑转移的推定介质。Rab11，a 内体再循环途径的组成部分，在适应大脑的过程中上调 微环境，表明参与脑转移的再循环。由于Rab 11调节特异性 囊泡货物在内体回收过程中，这一建议假设Rab 11介导乳腺癌 通过再循环介导的GABA受体上调的脑转移生长。拟议 研究将1）确定Rab 11在脑转移中上调的机制和后果; 2） 探讨Rab 11介导GABA受体再循环的机制; 3）研究靶向治疗的效果 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.