Michael Taylor

Dr Taylor obtained his MD at The University of Western Ontario in 1994; after which, he entered the Neurosurgery residency program at the University of Toronto.

During his residency training, he completed a PhD in Molecular Pathology at the University of Toronto (1998-2002), before concluding his residency training in 2003. That year, he was awarded a Detweiler Travelling Fellowship from the Royal College of Physicians and Surgeons of Canada for fellowship training in paediatric neurosurgery and paediatric neuro-oncology at St. Jude Children’s Research Hospital (SJCRH) in Memphis, Tennessee. While at SJCRH he also did a post-doctoral research fellowship in the Department of Developmental Neurobiology.

Dr Taylor joined The Hospital for Sick Children (SickKids), Division of Neurosurgery in 2004 and is a Senior Scientist in the Developmental & Stem Cell Biology Program at the SickKids Research Institute.

He is a principal investigator at the Arthur and Sonia Labatt Brain Tumour Research Centre and has cross-appointments in the Department of Surgery and the Department of Laboratory Medicine and Pathobiology at the University of Toronto.

Research in the Taylor Lab is supported by:

• the Canadian Institutes of Health Research (CIHR)
• Genome Canada
• National Cancer Institute of Canada
• Canadian Cancer Society
• National Institutes of Health (USA)
• American Brain Tumor Association
• SickKids Foundation.

Dr Taylor has published over 200 peer reviewed articles and his research focuses on using tools from human genetics/genomics, and from mouse and cell culture models to better understand the biology of pediatric brain tumours, particularly medulloblastoma and ependymoma.

As someone who is comfortable in both the clinic and at the bench, Dr Taylor offers much to the development of translational research for brain tumour research.

His team has previously described a number of the genetic events that are thought to drive the pathogenesis of paediatric brain tumours.

More recently, his group has developed functional genomic mouse models of medulloblastoma and ependymoma to help better interpret these genomic studies and provide avenues to new therapies via targeted translational research.

Research Synopsis

The Taylor Lab

I have a very large group of around 25 people, they cover the full gamut, including:

• co-op students
• research technicians
• graduate students
• post-doctoral fellows
• research associates
• a dedicated statistician
• project manager. 

This broad coverage allows us to tackle projects from multiple angles and provides a very productive and extremely collaborative environment. 

If you are interested in joining the team, please feel free to contact me directly.

Our laboratory space and bioinformatics offices are located together in the Arthur and Sonia Labatt Brain Tumour Research Centre (BTRC) which is part of the Developmental and Stem Cell Biology Program in the SickKids Research Institute. 

The BTRC comprises 8 principal investigators and occupies almost 15000 sq ft of space in the state of the art Peter Gilgan Centre for Research and Learning — the recently opened SickKids research tower.

In addition to the facilities available in the Labatt Brain Tumour Research Centre, SickKids has developed first-rate core facilities to support scientific enquiry. 

These include:

• Advanced Bioimaging Centre
• Advanced Protein Technology Centre
• Centre for Computational Biology
• Clinical Research Support Unit
• Clinical Research Centre
• Flow Cytometry Facility
• Mouse Imaging Facility
• The Centre for Applied Genomics
• Lab Animal Services
• Transgenic Facility
• Monoclonal Facility. 

My group also has a large number of mouse strains which are housed at the Toronto Centre for Phenogenomics (TCP), a state of the art animal facility with several full time veterinarians and ample resources to conduct mouse surgery and imaging required for our projects.

Our research

Research in my laboratory focuses on the study of paediatric brain tumours — specifically medulloblastoma and ependymoma.

Medulloblastoma is the most common malignant pediatric brain tumor, and a major cause of morbidity and mortality for children in Ontario and around the world, while ependymoma is the third most common malignant paediatric brain tumour.

Current therapies for these diseases can cure many of the patients, unfortunately, the treatments often leave survivors with serious intellectual, neurological, and physical disabilities. As such, there is an urgent need to develop new targeted therapies to improve the outcome for children with these tumours.

About 80% of the research in my laboratory is focused on the study of medulloblastoma, with the remaining 20% studying ependymoma.

Fortunately, my group is in an enviable position, as we have direct access to the tumours and sequencing data that form part of the Medulloblastoma Advanced Genomics International Consortium (MAGIC). MAGIC is a SickKids based consortium that consists of clinicians, scientists, and pathologists from over 75 cities around the world who have collectively contributed frozen medulloblastoma samples to the genomics efforts in Toronto.

This large sequencing project, funded by Genome Canada to perform RNA-Sequencing and Whole Genome Sequencing on medulloblastoma has recently been completed, and the original sequencing goals have all been met. We suspect that our dataset is the largest single RNA-Seq dataset on a specific cancer type that has been sequenced to date, and that it will represent a very rich source of data on medulloblastoma for our labs and for others in the years to come.

In fact, our previous publications using some of this data have shown that somatic single nucleotide variants (sSNVs) are uncommon in medulloblastoma (Pugh et al. Nature 2012, Jones et. al. Nature 2012, Kool et. al. Cancer Cell 2014) and suggest that targeting sSNVs using small molecules is unlikely to be the dominant form of rational therapy for medulloblastoma in the near future. However, our data also suggested that copy number variations/aberrations (CNAs) and structural variations are much more common than sSNVs in medulloblastoma (Northcott et. al. Nature 2012. Northcott et. al. Nature 2014).

Using a similar genomic approach with ependymoma, previous work from our group and others has shown that, similar to medulloblastoma, ependymoma are unique among lethal human malignancies in that they have no recurrent somatic mutations, and the lowest rate of mutation of any human cancers studied (Mack and Witt et. al. Nature 2014).

Clearly, the dream of precision medicine which entailed the sequencing of cancer genomes to identify sSNVs that are highly recurrent in a given tumour type, followed by the development and application of small molecule inhibitors that would be toxic to the tumour cells carrying the SNV, but harmless to normal cells, will not work for medulloblastoma or ependymoma.

With this in mind, we continue to analyse the genomic data (we have three dedicated ‘dry lab’ bioinformaticians) while using the previous findings to develop new animal and cell culture models.

We currently have numerous potentially highly impactful projects which use these newly developed models, including, using optogenetics and induced membrane depolarization, cerebelless mice, immunotherapy using chimeric antigen receptors and ‘synthetic vital’ high-throughput drug screening. Improving the therapy for children with brain tumours is a major goal of my research. 

We have published extensively on medulloblastoma (and to a lesser extent on ependymoma), and I am proud to say that our findings have had some impact on the care of children with this disease.

Recent Publications

Pugh TJ et al.  Medulloblastoma Exome Sequencing Uncovers Subtype-Specific Somatic Mutations Within a Broad Landscape of Genetic Heterogeneity. Nature 2012. 488(7409): 106-110

Northcott PA et al. Clinical Implications of Medulloblastoma Subgroups. Nature Reviews Neurology 2012. 8(6): 340-51.

Huang X et al.  Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics. Genes and Development 2012, 26(16): 1780-96

Taylor MD et al. Molecular Subgroups of Medulloblastoma: The Current Consensus. Acta Neuropathologica 2012. 123(4), 465-72.

Pei Y et al. An Animal Model of MYC-Driven Medulloblastoma. Cancer Cell 2012. 21(2), 155-167

Swartling FJ et al.  Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-myc. Cancer Cell 2012. Vol 21, 601-613.

Northcott PA, Shih DJH, Remke M, … Rutka JT, Korshunov A, Pfister S, Taylor MD. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathologica. 2012, 123(4), 615-26.

Wu X. et al.  2011. Disseminated medulloblastoma is bicompartmental secondary to clonal selection. Nature. 2012. vol 482 (529-33).

Witt H. et al.  Delineation of Two Clinically and Molecularly Distinct Subgroups of Posterior Fossa Ependymoma. Cancer Cell 2011. (20): 143-157.

Rausch, T et al. Genome sequencing of medulloblastoma brain tumors of childhood links chromopthripsis with TP53 germline mutations. Cell 2012. 148(1-2), 59-71.

Jones et al. ICGC PedBrain: Dissecting the genomic complexity underlying medulloblastoma. Nature 2012. 488(7409). 100-5

Northcott PA. et al. Subgroup-Specific Structural Variation Across 1000 Medulloblastoma Genomes. Nature. 2012. 488(7409): 49-56 (MDT is senior corresponding author)

Jones DTW. et al. Recurrent FGFR1 hotspot mutations represent a novel therapeutic target in childhood astrocytoma. In press, Nature Genetics, 2013

Sturm D. Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma. Cancer Cell 2012. Vol 22, 425-437

Northcott PA. et al. Medulloblastomics: The End of the Beginning. Nature Reviews Cancer 2012. 12(12): 818-34. MDT is co-corresponding author.

Leprivier G. et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translational elongation. Cell 2013. 153(1064-1079)

Ramaswamy V, Remke M, Bouffet E…. Taylor MD. Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncology, 2013. 14(12): 1200-7.

Remke M, Ramaswamy V, Peacock J, Shih DJ, … Taylor MD. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. Acta Neuropathologica, 2013. 126(6): 917-29.

Kleinman CL.  Fusion of TTYH1 with C19MC microRNA cluster drives the expression of brain specific DNMT3B isoform in the embryonal brain tumor ETMR. Nature Genetics 2013.  46(1): 39-44.

Jager N.  Hypermutation of the inactive X chromosome is a frequent event in cancer. Cell, 2013. 155(3): 567-81.

Kool M.  Genome Sequencing of SHH Medulloblastoma Predicts Age Dependant Response to Smoothened-Inhibition. Cancer Cell 2014.

Ramaswamy V, Remke M, Shih D…. Taylor MD, Bouffet E. Pre-diagnostic Interval in medulloblastoma is subgroup specific. Pediatric Blood and Cancer 2014. 61(7): 1190-4.

Hovestadt V, Jones DTW, Picelli S, Wang W, Kool M, Northcott PA, ….. Taylor MD, Brors B, Felsberg J, Reifenberger G, Borkhardt A, Lenrach H, Eils R, Yaspo ML, Korshunov A, Landgraf P, Zapatka M, Radlwimmer B, Pfister SM, Lichter P. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature, 2014, 510(7506):537-41.

Shih DJH, Northcott PA, Remke M, Korshunov A, Ramaswamy V, …Pfister SM, Taylor MD.  Cytogenetic Prognostication Within Medulloblastoma Subgroups. J Clin Oncol 2014, MDT is senior corresponding author.

Ramaswamy V, Remke M, Shih D, Wang X, Raybaud C, Tabori U, Hawkins C, Rutka J, Taylor MD, Bouffet E. Duration of the Pre-diagnostic Interval in Medulloblastoma is Subgroup Dependent. Pediatric Blood and Cancer. 2014, 61(7):1190-4

Rusert JM, Wu X, Eberhart CG, Taylor MD, Wechsler-Reya RJ. Medulloblastoma. Cancer Cell. 2014 Dec 8. 26(6):940-940.e1.

Mack SC, Witt H, Jager N, Zuyderduyn S, Jones DTW, …Pfister SM, Korshunov A, Taylor MD. Effective Epigenetic Therapy for CIMP+ve Ependymoma. Nature, 2014. MDT is senior-corresponding author.

Forget A, Bihannic L, Cigna SM, Lefevre C, Remke M, Barnat M, Dodier S, Shirvani H, Mercier A, Mensah A, Garcia M, Humbert S, Taylor MD, Lasorella A, Ayrault O. Shh signaling protects Atoh1 from degradation mediated by the E3 ubiquitin ligase Huwe1 in neural precursors. Developmental Cell, 2014, 23; 29(6):649-61.

He X, Zhang L, Chen Y, Remke M, ..., Wechsler-Reya R, Taylor MD, Lu QR. The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma. Nature Medicine, 2014; 20(9):1035-42.

Mille F, Tamayo-Orrego L, Lévesque M, Remke M, Korshunov A, Cardin J, Bouchard N, Izzi L, Kool M, Northcott PA, Taylor MD, Pfister SM, Charron F. The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors. Developmental Cell, 2014, 13;31(1):34-47

Ramaswamy V, Remke M, Taylor MD. An epigenetic therapy for diffuse intrinsic pontine gliomas. Nature Medicine, 2014, 20(12):1378-9.

Wang X, Dubuc AM , Ramaswamy V , Mack S ... , Pfister SM , Korshunov A , Taylor MD.. Medulloblastoma subgroups remain stable across primary and metastatic compartments. Acta neuropathologica, 2015, 129(3): 449-57. MDT is senior-corresponding author.

Faria CC , Golbourn BJ , Dubuc AM , Remke M , ... Smith CA , Taylor MD , Rutka JT. Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma. Cancer research, 2015, 75(1):134-46.

Shlien A, Campbell BB, de Borja R, ... Taylor MD, Pursell ZF, Pearson CE, Malkin D, Futreal PA, Stratton MR, Bouffet E, Hawkins C, Campbell PJ, Tabori U; for the Biallelic Mismatch Repair Deficiency Consortium. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nature Genetics, 2015, 47(3):257-62.

Therapy for Metastatic Sonic Hedgehog Medulloblastoma. Cancer Research. 2015. Cancer Research 2015. 75(1): 134-146.

Ramaswamy V, Remke M, Adamski J, Bartels U, Tabori U, Wang X, Huang A, Hawkins C, Mabbott D, Laperriere N, Taylor MD, Bouffet E. Medulloblastoma subgroup-specific outcomes in irradiated children: who are the true high-risk patients? Neuro Oncol. 2016, 18(2):291-7.

Turner KM , Deshpande V , Beyter D , …..Taylor MD , Kaushal S , Cavenee WK , Wechsler-Reya R , Furnari FB , Vandenberg SR , Rao PN , Wahl GM , Bafna V , Mischel PS. (2017). Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature. 543(7643): 122-125.

Johann PD , Erkek S , Zapatka M , … Taylor MD , Huang A , Aronica E , Bertoni A , Radlwimmer B , Pietsch T , Schüller U , Schneppenheim R , Northcott PA , Korbel JO , Siebert R , Frühwald MC , Lichter P , Eils R , Gajjar A , Hasselblatt M , Pfister SM , Kool M. (2016). Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes. Cancer cell. 29(3): 379-93.

Suryo Rahmanto A , Savov V , Brunner A , ….. Taylor MD , Cho YJ , Pfister SM , Kool M , Korshunov A , Swartling FJ , Sangfelt O. (2016). FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma. The EMBO journal. 35(20): 2192-2212.

Morrissy AS, Garzia L, Shih DJH, Zuyderduyn S, Huang X, …. Jabadao N, Bader GD, Jones JM, Malkin D, Marra MA. Taylor MD. (2016). Divergent clonal selection dominates medulloblastoma at recurrence. Nature. 529(7586): 351-7.

Chun HJ , Lim EL , Heravi-Moussavi A , …… Taylor MD , Mungall AJ , Moore RA , Ma Y , Jones SJ , Perlman EJ , Hirst M , Marra MA. (2016). Genome-Wide Profiles of Extra-cranial Malignant Rhabdoid Tumors Reveal Heterogeneity and Dysregulated Developmental Pathways. Cancer cell. 29(3): 394-406.

Thompson EM, Hielscher T, Bouffet E, Remke M, Luu B, ….Dirks P, Rutka JT, Korshunov A, Pfister SM, Packer RJ, Ramaswamy V, Taylor MD. (2016). Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. The Lancet. Oncology. 17(4): 484-95.

Tamayo-Orrego L , Wu CL , Bouchard N , Khedher A , Swikert SM , Remke M , Skowron P , Taylor MD , Charron F. (2016). Evasion of Cell Senescence Leads to Medulloblastoma Progression. Cell reports. 14(12): 2925-37.

Appointments

Senior Scientist, Developmental & Stem Cell Biology Program, SickKids Research Institute