FROM CANCER STEM CELLS TO BRAIN TUMOUR FORMATION: THE ROLE OF HEATR1 AND RIBOSOME BIOGENESIS

Abstract

Brain tumours are initiated by neoplastic transformation of brain cells followed by uncontrolled proliferation, and are driven by genetic mutations. Despite years of study towards increasing our understanding of their origin and development, the high recurrence rate and poor prognosis of brain tumours in general, and specially of glioblastoma multiforme (GBM), the most aggressive type, highlight the need for more efficient therapeutic approaches. According to the Cancer Stem Cell (CSC) hypothesis, tumour initiation and relapse might be caused by a subpopulation of cells with stem cell characteristics. Loss of the Drosophila melanogaster tumour suppressor Brat or its human orthologue, TRIM3, promotes brain tumour growth in the Drosophila brain and in GBM, respectively. To investigate molecular characteristics of brain CSCs, single-cell transcriptome data from brat brain tumour-initiating cells was obtained by the C. Barros laboratory (Diaz et al., in preparation), and is the foundation of this thesis’ studies. L(2)K09022, the conserved orthologue of human Heat Repeat Containing 1 (HEATR1) was identified as upregulated in brat tumour initiation cells, and selected for further investigation with the main aim of exposing its potential role in brain tumour development. I show here that HEATR1 is overexpressed in GBM and low-grade glioma, and in both GBM immortalised cells and patient-derived GBM stem cells (GSCs). Using the Drosophila brat model, GBM cell lines, and GSCs, I demonstrated that although L(2)K09022/HEATR1 is not required for malignant transformation of brain tumour initiating cells, it is necessary for their enlargement, proliferation and tumour growth. HEATR1 acts in brain CSCs to promote ribosome biogenesis and thus contributing to protein synthesis, tumour cell growth and proliferation. Its action is, at least in part, mediated by recruiting and enhancing the activity of the oncogene c-Myc in nucleoli, the sites of ribogenesis. These findings reveal HEATR1 as a novel brain tumourigenesis player and suggest that it may be as a potential future therapeutic target for GBM and possibly other brain tumours.