Background to research and synopsis
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.
Recent publications by supervisors that are relevant to the project
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.
Informal enquiries (email address of Director of Studies) and any web links that prospective applicants would be referred to: Dr Sigrun Lange, Senior Lecturer in Molecular Pathology, Lead of Tissue Architecture and Regeneration Research Group: [email protected]
Information on the supervisory team:
- Tissue Architecture and Regeneration Research Group
- Dr Pinar Uysal-Onganer
- Prof Jimmy Bell
- Dr Sigrun Lange
Candidates should normally have a minimum classification of 2.1 in their Bachelor Degree or equivalent and preferably a Masters degree. Applicants whose secondary level education has not been conducted in the medium of English should also demonstrate evidence of appropriate English language proficiency normally defined as IELTS: 6.5 (overall score with not less than 6.0 in any of the individual elements).
Please follow this link to apply for the programme most appropriate to your research, please note that the programme appears as MPhil on UCAS, however there is an option on the form to request PhD via MPhil, which is the standard route:
To make your application for (SLS5):
Interviews will be held in June/July 2019. The Studentship title is SLS5 Full Scholarship and Fee Waiver School of Life Sciences. Please include this in your application, you must also list the Project Code in order for us to allocate your application to the correct.