Brain Cancer @ Leeds

Stem Cells and Brain Tumour Research Group

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Research Overview

Our research aims to provide novel insight into tumour cell biology and potential drug targets in brain cancer. We are interested in elucidating the cellular heterogeneity in tumours, stem cell-like properties of cancer cells, and molecular pathways that regulate the balance between self-renewal and differentiation.

Aggressive brain tumours such as Glioblastoma multiforme are very difficult to treat due to their high complexity resulting from molecular and cellular diversity within a single tumour (intra-tumour heterogeneity), tumour heterogeneity across patients, tumour invasion (infiltration of tumour cells into the brain), and resistance to DNA-damaging therapy. Interestingly, many of these characteristics have been attributed to undifferentiated cells in brain tumours known as brain tumour stem cells (BTSCs). BTSCs that are resistant to therapy may expand from very few cells, thereby helping the cancer to reoccur after and during treatment. Therefore, eliminating BTSCs through specific therapy is a desirable goal that requires suitable molecular targets.

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Phenotypic Characterization of Brain Tumour Initiating Cells (BTICs)
(A–F) Expression of Nestin, Sox2, and Ki67 (A and C) decreases in cultured BTICs in the presence of BMP4 (50 ng/mL; B and D) whereas expression of GFAP and TuJ1 increases compared to nontreated cells (n.t., E and F); DAPI-stained nuclei (blue). Scale bar represents 25 μm.
(G) Quantitation of cell marker expression of GBM surgical specimens (mean, error bars represent the standard error of the mean) grown under BTIC conditions (blue columns), upon withdrawal of FGF/EGF (light blue columns), upon further addition of 10% serum (dark red columns), and under BTIC conditions plus BMP4 (red columns).
(H and I) H&E and Nestin staining on adjacent sections detecting GBM-1-derived tumor mass below the ventricle (V), 15 weeks postimplantation. Arrowheads illustrate tumor cells infiltrating the corpus callosum (CC) and striatum (S) of the mouse brain. Scale bars represent 500 μm.
(J) Higher-power image of Nestin-expressing tumor cells within the CC. Scale bar represents 20 μm.
Taken from Wurdak et al, Cell Stem Cell (2010) 6: p37-47

Our previous work has implicated several proteins such as TRRAP and TACC3 in BTSC maintenance, and importantly, clinical data also link these molecules to a poor disease outcome in brain tumour patients. Thus, we are investigating the biological role of these specific molecules in BTSCs using a spectrum of methods (e.g., RNA interference, cDNA overexpression, chemical inhibition).

At the same time, we aim to develop options for combination therapy, for example using combinations of small molecule inhibitors that render BTSCs vulnerable to treatment regimes used in clinical practice, including radiation- and oncolytic virus therapy. We are also using chemical compounds to induce differentiation in BTSCs and to study BTSC phenotypic plasticity and its implication(s) in brain tumourigeneis.

We are interested in investigating intra-tumour heterogeneity and the diversity of BTSC/non-BTSC phenotypes. To this end, we are using single cell profiling approaches that allow us to determine gene expression changes in individual cells. These approaches also allow us to study gene networks regulating self-renewal, differentiation, and malignant transformation (i.e., induced by viruses) in heterogeneous populations of ‘normal’ progenitor cells, for example derived from adult liver and kidney.

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