Rab GTPases as therapeutic targets in metastatic medulloblastoma?

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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.