Prof. Sebastian Brandner (Head of Division)
Institute of Neurology , UCL
Queen Square House
Professor of Neuropathology
Institute of Neurology
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
Doctor of Medicine
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.
Molecular Neuro-Oncology: comprehensive Neuro-oncology service for the National
Hospital (more than 200 tests annually) and for referring Hospitals (more than 1200 tests ). See our website for details molecular pathology tests). The tests are reported jointly with Dr Jaunmuktane
Diagnostic Neuro-oncology: In rotation with all other consultants in the department, we diagnose all surgical Neuropathology in the Department. We diagnose more than 1100 brain tumours and pituitary adenomas every year. All consultants in the department have the expertise to diagnose common and rare brain cancers and other surgical neuropathology cases. Soft tissue and haematological malignancies are routinely referred for expert second opinion.
Prion disease: On specific request, we carry out high risk post mortem examinations, in particualr to exclude or confiirm prion disease (Creutzfeld-Jakob Disease)
Peripheral Neuropathies: Together with Dr Jaunmuktane I diagnose approximately 120 peripheral nerve biopsies per year. Most peripheral Neuropathies are of inflammatory nature and we have developed considerable expertise and interest in the differential diagnosis of inflammatory neuropathies. A broad range of specialist techniques are used in the diagnosis of inflammatory neuropathies. We have a close interaction with the clinical team to discuss the investigation of each neuropathy individually (read more about the centre for Neuromuscular Diseases).
EORTC (European Organisation into Research and Treatment of Cancer)
EANO (European Association of Neuro-oncology International Collaboration for Cancer Reporting (ICCR): Member of guideline Committee
NICE Guideline committee (Brain tumours) member
British neuro-oncology society board member
British neuropathology society, co-opted member clinical practice group (CPC) and specialty advisory committee (SAC)
Interspecialty Committee on Molecular Pathology, committee member
Advisory Committee for Dangerous Pathogens ACDP, Co-opted member
London Cancer: Committee member
Operational steering group neuro oncology at the National Hospital (NHNN).
Training programme Director diagnostic neuropathology (pan- London)
Original publications neuro-oncology
1 Pathania M, Maestro N, De Jay N, Harutyunyan AS, Henderson S, Nitarska J, Mikael L, Richard-Loendt A, Zhang Y, Khazaei S, Ibrahim NS, Herrero J, Riccio A, Albrecht S, Brandner S, Kleinmann C, Jabado N, Salomoni P. H3.3K27M cooperates with p53 loss and PDGFRA gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas. Cancer Cell 2017; In press:
2 Amodeo V, A D, Betts J, Bartesaghi S, Zhang Y, Richard-Londt A, Ellis M, Roshani R, Vouri M, Galavotti S, Oberndorfer S, Leite AP, Mackay A, Lampada A, Stratford EW, Li N, Dinsdale D, Grimwade D, Jones C, Nicotera P, Michod D, Brandner S, Salomoni P. A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS. Cell reports 2017; 20: 411-26
3 Haston S, Pozzi S, Carreno G, Manshaei S, Panousopoulos L, Gonzalez-Meljem JM, Apps JR, Virasami A, Thavaraj S, Gutteridge A, Forshew T, Marais R, Brandner S, Jacques TS, Andoniadou CL, Martinez-Barbera JP. MAPK pathway control of stem cell proliferation and differentiation in the embryonic pituitary provides insights into the pathogenesis of papillary craniopharyngioma. Development 2017; 144: 2141-52
4 Benedykcinska A, Ferreira A, Lau J, Broni J, Richard-Loendt A, Henriquez NV, Brandner S. Generation of brain tumours in mice by Cre-mediated recombination of neural progenitors in situ with the tamoxifen metabolite endoxifen. Dis Model Mech 2016; 9: 211-20
5 Reuss DE, Kratz A, Sahm F, Capper D, Schrimpf D, Koelsche C, Hovestadt V, Bewerunge-Hudler M, Jones DT, Schittenhelm J, Mittelbronn M, Rushing E, Simon M, Westphal M, Unterberg A, Platten M, Paulus W, Reifenberger G, Tonn JC, Aldape K, Pfister SM, Korshunov A, Weller M, Herold-Mende C, Wick W, Brandner S, von Deimling A. Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neuropathol 2015; 130: 407-17
6 Bartesaghi S, Graziano V, Galavotti S, Henriquez NV, Betts J, Saxena J, Minieri V, A D, Karlsson A, Martins LM, Capasso M, Nicotera P, Brandner S, De Laurenzi V, Salomoni P. Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells. Proc Natl Acad Sci U S A 2015; 112: 1059-64
7 Henriquez NV, Forshew T, Tatevossian R, Ellis M, Richard-Loendt A, Rogers H, Jacques TS, Reitboeck PG, Pearce K, Sheer D, Grundy RG, Brandner S. Comparative expression analysis reveals lineage relationships between human and murine gliomas and a dominance of glial signatures during tumor propagation in vitro. Cancer Res 2013; 73: 5834-44
8 Jacques TS, Swales A, Brzozowski MJ, Henriquez NV, Linehan JM, Mirzadeh Z, C O, Naumann H, Alvarez-Buylla A, Brandner S. Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes. EMBO J 2010; 29: 222-35
Original publications neurodegeneration
9 Mok T, Jaunmuktane Z, Joiner S, Campbell T, Morgan C, Wakerley B, Golestani F, Rudge P, Mead S, Jager HR, Wadsworth JD, Brandner S, Collinge J. Variant Creutzfeldt-Jakob Disease in a Patient with Heterozygosity at PRNP Codon 129. N Engl J Med 2017; 376: 292-4
10 Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J, Launchbury F, Linehan J, Richard-Loendt A, Walker AS, Rudge P, Collinge J, Brandner S. Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy. Nature 2015; 525: 247-50
11 Gill ON, Spencer Y, Richard-Loendt A, Kelly C, Dabaghian R, Boyes L, Linehan J, Simmons M, Webb P, Bellerby P, Andrews N, Hilton DA, Ironside JW, Beck J, Poulter M, Mead S, Brandner S. Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey. BMJ 2013; 347: f5675
12 Brandner S, Jaunmuktane Z. Prion disease: experimental models and reality. Acta Neuropathol 2017; 133: 197-222
13 Brandner S, von Deimling A. Diagnostic, prognostic and predictive relevance of molecular markers in gliomas. Neuropathol Appl Neurobiol 2015; 41: 694-720
14 Brandner S. Nanog, Gli, and p53: a new network of stemness in development and cancer. EMBO J 2010; 29: 2475-6
Books and guidelines
15 Brandner S. Neuronal and mixed neuronal–glial tumours (paraganglioma). In WHO Classification of Tumours of the Central Nervous System Eds. DN Louis, H Ohgaki, OD Wiestler, WK Cavenee, 5th edn. Lyon: WHO Press. 2016