About the Project
Glioblastoma multiforme (GBM) is the most common and aggressive form of primary malignant brain tumour in adults, with poor prognosis. Extracellular vesicles (EVs) are key-mediators for cellular communication through transfer of proteins and genetic material. Cancers, such as GBM, use EV release for drug-efflux, pro-oncogenic signalling, invasion and immunosuppression; thus the modulation of EV release and changes in EV cargo, including microRNAs, are of considerable clinical relevance.
Our recent publications show that EV release in GBM and other cancers can be targeted via the Peptidylarginine-deiminase (PAD) mediated pathway and by Cannabidiol (CBD) and that these may work in synergy, albeit via different mechanisms. We have shown both changes in amounts of EVs released, as well as a shift of a pro-oncogenic to an anti-oncogenic microRNA signature in GBM in response to PAD-inhibitor and CBD treatment.
The proposed project will establish how EV subpopulations and key-microRNAs can be selectively modulated with single or combinatory EV-inhibitors, to increase GBM susceptibility to therapy. Furthermore, changes in selected mitochondrial, nuclear and invadopodia related proteins will be investigated.
This project will create a platform for enhanced treatment efficacy in GBM and may also be translatable to other types of cancer.
The student will learn a range of state-of the art skills relating to extracellular vesicle and microRNA analysis and take part in the University Graduate School and College Doctoral Research Development Programme.
Informal enquiries to: Dr Sigrun Lange [Email Address Removed];
Information on the supervisory team:
Kosgodage, US, Uysal-Onganer P, MacLatchy A, Nicholas AP, Inal JM, Lange S (2019). Peptidylarginine Deiminases Post-translationally deiminate Prohibitin and modulate Extracellular Vesicle Release and microRNAs in Glioblastoma Multiforme. Int J Mol Sci 20(1):103.
Kosgodage US, Uysal-Onganer P, MacLatchy A, Mould R, Nunn AV, Guy GW, Kraev I, Chatterton NP, Thomas EL, Inal JM, Bell JD, Lange S (2019). Cannabidiol Affects Extracellular Vesicle Release, miR21 and miR126, and Reduces Prohibitin Protein in Glioblastoma Multiforme Cells. Transl Oncol. 12(3):513-522.
Kosgodage US, Mould R, Henley AB, Nunn AV, Guy GW, Thomas EL, Inal JM, Bell JD, Lange S (2018). Cannabidiol (CBD) Is a Novel Inhibitor for Exosome and Microvesicle (EMV) Release in Cancer. Front Pharmacol. 9:889.
Kosgodage US, Trindade RP, Thompson PT, Inal JM, Lange S (2017). Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy. Int J Mol Sci.18(5).
Lange S, Gallagher M, Kholia S, Kosgodage US, Hristova M, Hardy J, Inal JM (2017). Peptidylarginine Deiminases – Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release? Int J Mol Sci. 18(6): 1196.
Kholia S, Jorfi S, Thompson PR, Causey CP, Nicholas AP, Inal J, Lange S (2015). A Novel Role for Peptidylarginine Deiminases (PADs) in Microvesicle Release: A Therapeutic Potential for PAD Inhibitors to Sensitize Prostate Cancer Cells to Chemotherapy. J Extracellular Vesicles; 4:26192.