Staff: 

  • Susanna Chan 
  • Jungeun Song 

Trainees: 

  • Veronique LeBlanc, PhD Candidate 

    • Glioblastomas (GBMs) account for nearly half of all primary malignant brain tumours, and current therapies are often only marginally effective. Our understanding of the underlying biology of these tumours and the development of new therapies have been complicated in part by widespread inter- and intratumoural heterogeneity. To explore this heterogeneity, we are performing regional subsampling of primary glioblastomas and organoids derived from these tissue samples. To identify cellular subpopulations within these tissues and organoids, we are performing single-cell RNA-sequencing (scRNA-seq) and genome sequencing on primary tumour samples and 1-3 matched organoids per sample. We have profiled samples from five tumour sets to date and have obtained sequencing data for 16,822 primary tissue cells and 11,043 organoid cells. Overall, our data will help evaluate the utility of tumour-derived organoids as model systems for GBM and will aid in identifying cellular subpopulations defined by gene expression patterns, both in primary GBM regional subsamples and their associated organoids. These analyses may also uncover novel therapeutic targets previously unrevealed through bulk analyses.

  • Ishikia Luthra, Co-op Student 

    • Glioblastoma (GBM) is the most common and aggressive primary brain tumour, and is characterized by dismal patient outcomes.  Such outcomes reveal (1) the lack of effective treatments for GBM patients; (2) the need for advances in our understanding of disease biology, and (3) the need for improved models to explore disease biology and drug development. To address these needs, we are studying patient derived organoids as models of GBM, using single cell sequencing to compare and contrast, at the DNA and RNA levels, genomic properties of tumor cells and organoid cells. Using software design and statistical analysis we develop high-throughput large-scale data pipelines to probe genomic heterogeneity across individual glioma- and patient-derived organoid cells. This heterogeneity is measured and quantified at both the DNA and RNA levels to: describe detailed intra- and inter- tumoral heterogeneity landscapes at the single cell level; assess the extent to which tumour heterogeneity is captured within organoids; capture observations of biological or therapeutic relevance.

  • Stephen Lee, PhD Candidate 

    • CIC, or Capicua, encodes a transcriptional repressor that is itself repressed by RAS/MAPK signalling. CIC is a target of somatic mutation in 50-70% of type 1 low grade gliomas (LGG), with at least half of the alterations predicted to be deleterious. Type 1 LGGs are a cohort of tumours that are molecularly defined by the loss of heterozygosity of chromosome arms 1p and 19q and the presence of neomorphic IDH1/2 mutations. Despite the high frequency of mutations in CIC within this tumour type, CIC’s putative tumour suppressive role remains to be elucidated. It is also unclear how CIC may cooperate with neomorphic IDH1/2 to promote gliomagenesis. To comprehensively characterize the molecular consequences of CIC loss, we are performing RNA-seq, whole genome bisulfite sequencing, and ChIP-seq on isogenic CIC-wildtype (WT) and CIC-knockout (KO) normal human astrocytes, with and without IDH1 R132H mutations. Integrative analyses are ongoing to unveil the epigenetic mechanisms underpinning the regulatory changes in these isogenic cell line models.

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