Decoding mechanisms of brain tumour initiating cell adaption and tumour growth

Abstract

Despite the many therapeutic advances in oncology in the last few decades, glioblastoma (GBM) remains the most common malignant brain tumour with only 5% and 0.76% of patients surviving for 5 and 10 years beyond diagnosis, respectively. The cancer stem cell subpopulation of such tumours has been shown to be responsible for tumour initiation and to be able to recapitulate tumours upon transplantation into healthy hosts. These tumour (re)-initiation cells exhibit stem-like characteristics which positively correlate with higher brain tumour grade and worse clinical prognosis. The glioma stem cells (GSCs) in GBMs are responsible for therapeutic resistance and tumour recurrence. Loss of the TRIM3 tumour suppressor in human brains increases stem-like properties, promotes oncogenic symmetric cellular divisions and triggers brain tumour growth. The conserved Drosophila orthologue of TRIM3 is brain tumour (brat). A single-cell transcriptome analysis carried out by the Barros laboratory identified differentially expressed genes between Drosophila brat tumour-initiating cells (TICs) versus their control immature Intermediate Neural Progenitors (iINPs) counterparts. One such gene was CG1671 which was found to have upregulated expression in brat-deficient TICs. The human orthologue of CG1671 is Transducin β-like 3 (TBL3). In this work, both genes are referred to as ‘TBL3’ for simplicity. Although the TBL3 nucleolar protein has only been recently implicated in ribosome biogenesis (ribogenesis) of human cells, its potential role(s) in tumour development remained unexposed. This PhD project aimed to reveal such possible role(s) of TBL3 in brain tumour development, as well as expand on expression analysis profiling of a subset of human orthologues to expose candidates differentially expressed in gliomas and GSCs versus their respective controls.

In this study, I show that TBL3 is overexpressed in low- and high-grade gliomas compared to control brains, and in propagating glioma stem cells (GSCs) compared to non-tumourigenic human foetal neural stem cells and differentiated GSCs. Strikingly, reduced TBL3 levels in GSCs diminishes their tumourigenic capacity and proliferation. In brat-deficient brain lobes, TBL3 knockdown decreases proliferation rate, triggers maturation, and drives cells to express neuronal and glial markers. TBL3 is therefore proposed as a potential new player in brain tumour initiation and growth that could serve as a future therapeutic target for GBM and other highly proliferative brain tumours.