Abstract
Although brain tumours kill more people under the age of 40 than any other cancer, and glioblastoma (GBM) is the most common malignant brain tumour, effective brain cancer treatments are not available. The Cancer Stem Cell theory dictates that a subset of cells within a tumour have self-renewal potential and are responsible for tumour formation. GBM stem cells (GSCs) are resistant to conventional therapy and can reform GBM tumours. The Drosophila brain tumour (brat) model is widely used in the study of brain tumourigenesis. Brat determines the fate of intermediate neural progenitors (INPs) in Drosophila brains, acting as a tumour suppressor. Its inhibition causes INP transformation into tumour initiating cells and malignant tumour overgrowth. The human brat orthologue TRIM3 is also described as a tumour suppressor in GBM. A single cell transcriptome analysis by the Barros laboratory identified Yeast Mitochondrial Escape 1-Like (YME1L) upregulated in brat brain tumour initiating cells (Barros laboratory, unpublished). YME1L is a metalloprotease involved in mitochondrial dynamics and respiration, and was recently implicated in proliferation and stemness of mouse neural stem progenitor cells. However, it has not been associated with brain tumours to date. This PhD project aimed to demonstrate YME1L’s potential role in brain tumourigenesis. The findings I describe demonstrate that, in Drosophila and GSCs, YME1L is essential for tumour cell stemness, proliferation and survival. Upon YME1L inhibition, brat-deficient tumour initiating cells differentiate and lose tumourigenic potential. Mitochondrial membrane potential, an indicator of oxidative metabolism, also decreases upon YME1L inhibition in GSCs. Inhibiting YME1L fragments the mitochondrial network in both Drosophila and GSCs. Strikingly, rescue of this effect in GSCs via overexpression of the fusion protein Mitofusin 2 restores their proliferative capacity. Based on these data, a model is proposed in which YME1L-dependent mitochondrial dynamics promotes brain tumour initiation and growth. YME1L is identified as a novel contributor to brain tumourigenesis and may be a potential therapeutic target in future treatments of GBM.
Document Type
Thesis
Publication Date
2023-01-01
DOI
10.24382/5060
Recommended Citation
Pugh, J. (2023) Investigating the Role of YME1L in Brain Tumour Initiation and Growth. Thesis. University of Plymouth. Available at: https://doi.org/10.24382/5060
