LIMR Cancer Biology: The role of Wnt signalling in glioblastoma therapeutic resistance

Summary

Glioblastoma is a deadly brain tumour treated with surgery, radiotherapy and chemotherapy with patient survival of 6-15 months. Our previous work investigated changes in the microenvironment of glioblastoma tumours that have become resistant to radiotherapy, using patient samples and an in vivo model of glioblastoma recurrence following radiotherapy. We found vascular changes in recurrent tumours that elevate hypoxia, thus promoting invasiveness to the normal brain and resistance to further treatment. RNA sequencing revealed upregulation of ligands that activate Wnt signaling, associated with altered blood vessel morphology and function. During normal development Wnt ligands bind Frizzled and other receptors to control gene transcription, proliferation and differentiation. Deregulation of Wnt signaling in cancer cells, or the tumour microenvironment (immune cells, fibroblasts, blood vessels) is associated with malignancy. Our aim is to understand the role of Wnt ligands in glioblastoma recurrence using knockdown and overexpression approaches employing 3-dimensional culture and in vivo recurrence models established in our lab. Furthermore, we will analyze differential ligand expression in patient samples of primary and recurrent glioblastoma tumours (paired). We will assess the efficacy of Wnt inhibitors in combination with radiotherapy, aiming to improve response to radiotherapy and survival of patients with recurrent glioblastoma.

Techniques associated with this project:

The student will gain experience in a wide range of techniques and approaches including CRISPR, western blotting, RNA sequencing, culture model of perfused endothelial tubes in microfluidic devices, in vivo model of radiotherapy treatment, confocal imaging, immunohistochemical and immunofluorescence analysis of patient samples, Image J software analysis.

This project is part of the International PhD Academy: Medical Research

In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.