Stem Cells and Brain Tumour Group

Group Leader: Dr Heiko Wurdak

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.

Research Areas

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.

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.

People

Heiko Wurdak, PhD (PI/Group Leader) - h.wurdak@leeds.ac.uk
Anjana Patel, PhD (Post-Doctoral Fellow) - a.patel@leeds.ac.uk
Euan Polson, PhD (Post-Doctoral Fellow) - e.polson@leeds.ac.uk
Verena Kuchler (PhD Student) - v.b.kuchler@leeds.ac.uk
Jennifer Williams (Research Technician) - j.h.williams@leeds.ac.uk

Publications

Wurdak H. (2012) Exploring the cancer stem cell phenotype with high-throughput screening applications. Future Med Chem 4 (10):1229-41.

Wurdak H., Zhu S., Min K.H., Aimone L., Lairson L.L., Watson J., Chopiuk G., Demas J., Charette B., Halder R., Weerapana E., Cravatt B.F., Cline H.T., Peters E.C., Zhang J., Walker J.R., Wu C., Chang J., Tuntland T., Cho C.Y., Schultz P.G. (2010). A small molecule accelerates neuronal differentiation in the adult rat. PNAS 107 (51):22360.

Wurdak H., Zhu S., Romero A., Lorger M., Watson J., Chiang C., Zhang J., Natu V.S., Lairson L.L., Walker J.R., Trussell C.M., Harsh G.R., Vogel H., Felding-Habermann B., Orth A.P., Miraglia L.J., Rines D.R., Skirboll S.L., Schultz P.G. (2010) An RNAi Screen identifies TRRAP as a regulator of brain tumor-initiating cell differentiation. Cell Stem Cell 8;6(1):37-47.

Zhu S., Wurdak H., Wang J., Lyssiotis C.A., Peters E.C., Cho C.Y., Wu X., Schultz P.G. (2009) A small molecule primes embryonic stem cells for differentiation. Cell Stem Cell 4 (5): 416-26.

Falk S., Wurdak H., Ittner L.M., Ille F., Sumara G., Schmid M.T., Draganova K., Lang K.S., Paratore C., Leveen P., Suter U., Karlsson S., Born W., Ricci R., Götz M., Sommer L. (2008) Brain area-specific effect of TGF-beta signaling on Wnt-dependent neural stem cell expansion. Cell Stem Cell 2 (5): 472-83.

Funding

Research in our laboratory is currently funded by the MRC (New Investigator Research Grant), AICR (Project Grant), European Commission FP7 (Marie Curie Career Integration Grant), and the Leeds CRUK centre (Development Fund).

Studentships

Please see www.FindaPhD.com or the Faculty Graduate School pages for research projects within the Stem Cells and Brain Tumour Group.

Related Links

Centre Membership

Leeds Cancer Research UK Centre

Biomedical Health Research Centre (BHRC)

Neuro-oncology at Leeds