Screening for Novel Brain Tumour Initiation Mechanisms at Single Cell Resolution

Jaworek, Karolina (2016) Screening for Novel Brain Tumour Initiation Mechanisms at Single Cell Resolution. PhD thesis, Prifysgol Bangor University.

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Despite progress in our understanding of origin and development of brain tumours, more efficient therapeutic approaches addressing the high recurrence rate and poor prognosis of brain tumours remain urgently needed, in particular for the most aggressive glioblastomas (GBMs). In this work, I used the Drosophila brain tumour (brat) mutant as an in vivo model to identify potential mechanisms of brain tumour initiation. The human brat orthologue, Trim3, has a conserved tumour suppressor function in GBMs. I applied a single cell transcriptome microarray technique to compare intermediate neural progenitor cells harvested from live brat versus control larval brains, at a developmental stage when the first signs of molecular transformation into tumour initiation cells are observed in the mutants but no over-proliferation can yet be detected. I identified 1132 transcripts differentially expressed (threshold: -0.5Log2FC0.5). My gene ontology-based analysis revealed that metabolic pathways, RNA processing and protein synthesis are among the most represented functional categories. I validated the screen data via qPCRs, and translated gene expression findings into human GBM tissues and cell lines. I found 21 out of 24 human orthologue transcripts tested to be also differentially expressed in GBMs compared to control human brain tissues, suggesting the possibility of conserved roles. Finally, I examined in more detail selected individual transcripts. Of note, I showed that loss of two candidates found upregulated in brain tumour initiation cells and in GBMs, mob3 and l(2)k09022, causes severe impairment of normal postembryonic neural stem cell proliferation. I also demonstrated that another candidate, YME1L1, which contributes to mitochondrial proteostasis and respiration, is up regulated in tumour initiation cells and in GBMs at both mRNA and protein levels, suggesting it may promote tumour initiation by altering mitochondria function. In summary, the work I developed lays an original foundation for future studies of brain tumour initiation mechanisms.

Item Type: Thesis (PhD)
Additional Information: No permission for electronical availability
Subjects: Degree Thesis
Departments: College of Natural Sciences > School of Biological Sciences
Degree Thesis
Date Deposited: 11 Jan 2017 15:58
Last Modified: 11 Jan 2017 15:58
URI: http://e.bangor.ac.uk/id/eprint/9783
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