Aims Our research is focused on neural stem cells. We would like to determine the role played by transcriptional and epigenetic mechanisms in establishing and sustaining neural stem cell identity. New knowledge in this area will aid our understanding of human forebrain development and provide a foundation for future regenerative medicine.
We also study the human brain cancer, glioblastoma. Cells displaying neural stem cell characteristics drive the growth of these tumours. We hope knowledge from neural stem cell biology will help uncover new therapeutic targets for this devastating disease.
Image shows neural stem cells differentiating into astrocytes and oligodendrocytes.
Approach and progress Our primary model system is a novel set of neural stem (NS) cell lines generated from rodent and human germinal tissues or from brain tumour biopsies. These in vitro studies are complemented by in vivo assays (stereotaxic injection) and analysis of the developing mouse forebrain and primary tumour samples.
There are currently three major areas of interest:
Lineage specific transcription factors We are investigating the function and biochemistry of lineage specific transcriptional regulators, such as members of the SOX, FOX and bHLH family. These lie at the heart of cell fate decisions in neural stem and progenitor cells during development and within brain tumours.
Chemical and genetic screening We are carrying out image-based small molecule screens to search for new agents and pathways that can modulate self-renewal and differentiation in normal and glioblastoma-derived neural stem cells. We are exploiting the latest genome editing technologies to create novel defined human cellular models of brain cancer stem cells.
Epigenetic programming and reprogramming We are investigating whether changes to the epigenome within glioblastoma-derived cancer stem cells enable suppression of malignant properties. We are using both direct differentiation as well as nuclear reprogramming strategies to test this.
Danovi D, Folarin A, Ender C, Elbatsh A, Engstrom PG, Gogolok S, Stricker SH, Yu D, KP U, Harvey KJ, Ferretti P, Paddison P, Bertone P, Smith A, Pollard SM. 2013. A high-content small molecule screen identifies sensitivity of glioblastoma stem cells to inhibition of polo-like kinase. PLoS One 8(10):e77053.
Stricker SH, Feber A, Kurian KM, Engstrom P, Tatashima Y, Watts C, Dirks P, Bertone P, Beck S, Smith A, Pollard SM. 2013. Widespread resetting of DNA methylation in glioblastoma initiating cells suppresses malignant cellular behaviour in a lineage dependent manner. Genes Dev. 27(6):654-69.
Danovi D, Folarin A, Baranowski B, and Pollard SM. 2012. High content screening of defined chemical libraries using normal and glioma-derived neural stem cells lines. Methods in Enzymol. 506:311–329.
Carén H, Pollard SM, Beck S. 2012. The good, the bad and the ugly: Epigenetic mechanisms in glioblastoma. Mol. Aspects Med. 34(4):849-62.
Pollard SM, Yoshikawa K, Clarke I, Danovi D, Stricker S, Russell R, Bayani J, Head R, Lee M, Bernstein M, Squire J, Smith A and Dirks P. 2009. Glioma stem cell lines expanded in adherent culture have tumour-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell 4(6):568-80.