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Rab GTPases as therapeutic targets in metastatic medulloblastoma?

Rab GTPases 作为转移性髓母细胞瘤的治疗靶点？

基本信息

批准号：
2275082
负责人：
金额：
--
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2275082
关键词：
Rab GTPases therapeutic targets metastatic

项目摘要

Medulloblastoma is the most common malignant paediatric brain tumour. Over one-third of tumours are metastatic at diagnosis and almost all patients have metastases at relapse. Currently, there is no curative treatment for patients with metastatic medulloblastoma, which is underdiagnosed by current techniques. To improve diagnosis and treatment a greater understanding of the mechanisms of metastasis is required, as is the development of newer diagnostic methods. Extracellular vesicles (EVs) are a heterogeneous population of nano-sized, cell derived vesicles. EVs have been shown to transfer oncogenic proteins and nucleic acid cargo to recipient cells, which modulates their activity, and plays a decisive role in tumorigenesis. Rab GTPases, are a large family of small GTPases that control vesicle budding, motility and fusion. Many studies have linked Rab GTPases with both cancer progression and metastasis, although their role in medulloblastoma has yet to be defined. There is also evidence that Rab GTPases regulate packaging and release of exosomes. Our research has shown that a greater number of exosomes are released from metastatic medulloblastoma cell lines in comparison to their non-metastatic counterparts. We have also show that the contents of the exosomes released from metastatic and non-metastatic tumours differ with metastatic cells releasing exosomes that contain mRNAs linked with drug resistance and cell migration. If these features are regulated by Rab GTPases then targeting these proteins would represent a novel therapeutic strategy in metastatic medulloblastoma.The aim of this project is to test the hypothesis that specific Rab GTPases regulate the release and contents of extracellular vesicles (EVs) in medulloblastoma metastasis.

髓母细胞瘤是最常见的儿童恶性脑肿瘤。超过三分之一的肿瘤在诊断时是转移性的，几乎所有患者在复发时都有转移。目前，没有治愈性治疗转移性髓母细胞瘤患者，这是诊断不足，由目前的技术。为了改善诊断和治疗，需要更好地了解转移的机制，以及开发新的诊断方法。细胞外囊泡（EV）是纳米尺寸的、细胞衍生的囊泡的异质群体。EV已被证明可将致癌蛋白和核酸货物转移到受体细胞，从而调节其活性，并在肿瘤发生中起决定性作用。Rab GTP酶是控制囊泡出芽、运动和融合的小GTP酶的大家族。许多研究已经将Rab GTP酶与癌症进展和转移联系起来，尽管它们在髓母细胞瘤中的作用尚未确定。还有证据表明Rab GTP酶调节外泌体的包装和释放。我们的研究表明，与非转移性对应物相比，转移性髓母细胞瘤细胞系释放出更多数量的外泌体。我们还表明，从转移性和非转移性肿瘤释放的外来体的内容物与释放含有与耐药性和细胞迁移相关的mRNA的外来体的转移性细胞不同。如果这些功能是由Rab GTP酶调节的，那么靶向这些蛋白将代表一种新的治疗策略在转移性髓母细胞瘤。本项目的目的是测试的假设，即特定的Rab GTP酶调节细胞外囊泡（EV）的释放和内容在髓母细胞瘤转移。