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Title: Molecular regulation of glioma cell migration : assessment and therapeutic implications
Author: Gessler, Florian
ISNI:       0000 0004 8501 4443
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Molecular regulation of glioma cell migration: assessment and therapeutic implications Florian Gessler Glioblastomas are among of the most aggressive human tumour types. Overall survival in patients with this malignancy is no longer than 18 months despite receiving extensive therapy. The development of a targeted glioblastoma therapy and immunotherapy are currently implemented as possible alternative treatments in patients with recurrent glioblastoma. Furthermore, emerging evidence indicates that the CD142/PAR-2 cascade is implicated in glioblastoma proliferation, invasion and migration. Recent data suggest that CD142 play a crucial oncogenic role in various tumours via the PAR-2 pathway which is capable of modulating the ERK cascade through ARR1. Results illustrated the co-localization of PAR-2, ARR1 and the ERK module, including RAF, MEK, and ERK at the cell membrane following PAR-2 stimulation, suggesting that activation of PAR-2 contributes to the recruitment of ARR1 to PAR-2, which leads to further assembly of the ERK module followed by sequential phosphorylation of the ERK cascade. In further investigations on the role of ARR1 in driving cell migration, depletion of ARR1 by stable lentiviral shRNA drastically diminished the in vitro motility of glioblastoma cells, suggesting that ARR1 is indeed essential for glioblastoma migration. Next to the detection of high levels of CD142 in tumour cells, CD142 has been detected in tumour cell-derived extracellular vesicles. In recent years, a number of studies have described that extracellular vesicles might hold a remarkable potential in regenerative medicine by acting as therapeutically distinct nanodrugs. The understanding of their final impact on the biology of specific target cells, as well as the clarification of their overall therapeutic impact remains a matter of intense debate . Biogels have been widely used in medical devices and for the release of several drugs and appear to be an ideal carrier for the local application of vesicles. These merits are highly desired for a broad spectrum of in vivo applications and offer the potential to improve the performance of medical devices for the CNS, where a foreign body reaction is an undesirable event preventing long-term performances of devices intended for the treatment of chronic diseases. Promising results obtained over the last decades highlight EVs as candidates for therapeutic approaches in regenerative medicine and oncology.
Supervisor: Pluchino, Stefano Sponsor: Gates Cambridge
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: CD142 ; miR-155 ; Extracellular vesicles