Prof Sebastian Brandner
Professor of Neuropathology
Institute of Neurology
- Joined UCL
- 1st Oct 2004
Modelling intrinsic brain tumours: Oncogenic signalling in neural stem cells
Intrinsic benign and malignant brain tumours, such as astrocytomas and glioblastoma are thought to originate from a population of stem cells in the adult brain. Stem cells divide in the adult brain to form more mature cells such as nerve cells (neurones) astrocytes (supporting cells) or oligodendrocytes (myelin forming cells that wrap processes of neurones in the white matter). We are working on the mechanisms of how mutations in genes that control cell division and migration of stem cells can cause brain tumours.
A novel aspect of our work is that the type of tumours depends on the pattern of mutations in stem cells, even when mutated stem cells are taken away from their normal environment and are placed in other areas of the brain. Knowledge of this mechanism is an important step towards the understanding where brain tumours originate from and how a certain type of brain tumour forms.
How does the model work?
We inactivate tumour suppressor genes (PTEN, RB, p53) in the neural stem cell compartment. By injecting Cre-expressing virus into the ventricles of conditional knockout mice (PTENlox/lox, p53lox/lox and Rblox/lox in various combinations) the targeted genes are recombined only in cells located near the sub-ventricular zone (SVZ) which contains the largest known population of neural stem cells. In mice where Rb and p53, or the trio of the genes, PTEN, P53 and Rb are recombined, after several months, tumours of a specific phenotype resembling that of a human PNET develop. Instead, a tumour resembling human glioma (similar to oligoastrocytomas) is induced in mice where PTEN and P53 are targeted
Several weeks to months prior to the development of large tumours, small neoplastic lesions can be observed which we call microneoplasia. The assumption is that during the considerable time it takes to develop evident tumours additional genetic lesions are accumulated on top of the ones induced by Cre-recombination
- Georg-August-Universität Göttingen
- Priv-Doz, Clinical Medicine | 1991
- Georg-August-Universität Göttingen
- MD, Clinical Medicine | 1989
I started my research career during Medical School in Göttingen, at the Max Planck Institute of Biophysical Chemistry with Professor Creutzfeldt, where I studied the projection of the thalamocortical auditory system in the cat, resulting in several research publications as first author.
During my postgraduate training in Neuropathology, I joined the Institute of Neuropathology in Zurich, where I started my research on prion disease, resulting in seminal publications in Nature and PNAS.
After qualifying as a Consultant Neuropathologist in 1998, I established my own research group and developed mouse models to study neural development and brain tumours. In 2001, I was recruited through the MRC international recruitment scheme to join the MRC Prion Unit at UCL Institute of Neurology.
In 2004 I was appointed as Chair of Neuropathology and Head of the Division of Neuropathology at Queen Square, one of the largest academic neuropathology departments in the UK.
At the MRC Prion Unit and the Institute of Neurology I integrated clinical neuropathology with experimental models on neurodegenerative diseases including prion diseases, which still remain a strong focus in my highly collaborative research. I am an expert on the pathology of both human and experimental models of prion disease worldwide and I maintains a close collaboration with the MRC Prion Unit and the National Prion Clinic at the National Hospital, Queen Square.
I recently conducted a study “prevalence screening for the presence of vCJD prions” for the HPA, which has major implications for UK policy. At the Institute of Neurology, I also expanded my research on brain tumours which resulted in a number of excellent publications in Development and EMBO Journal. I developed a strong team working on brain cancer, and established close collaborations between UCL Cancer Centre and the Brain Tumour Unit at the National Hospital. I contribute nationally to brain cancer research in my role as council member of the British Neuro-oncology Society. Academic pathology and research on experimental models and their translation to human diseases are recognised key development areas in the UK.