Professor Denise Sheer, BSc, BSc(Hons), D.Phil.

Profile

Denise Sheer completed a B.Sc (Hons) in Embryology and Zoology at the University of the Witwatersrand, Johannesburg, and then ran the diagnostic Cytogenetics Laboratory at the South African Institute of Medical Research for two years. She then moved to the Genetics Laboratory at the University of Oxford, where she was awarded a D.Phil.  After a Post-Doctoral Research Fellowship at the Imperial Cancer Research Fund (Cancer Research UK), she became Head of the Human Cytogenetics Laboratory, where her group identified significant genetic aberrations in many different malignancies and made critical discoveries on chromosome architecture. She moved with her group to the Blizard Institute in 2006.

Member of the Children’s Cancer and Leukaemia Group

Member of the British Neuro-Oncology Society

Member of the European Society for Paediatric Oncology

Jeremy Jass Prize for Excellence in Pathology 2009 – awarded for the discovery of RAF gene fusions in children’s brain tumours.

Queen Mary Innovation Proof of Concept Award 2015 for discoveries made on protein aggregation and neurodegenerative diseases.

Summary

Professor Sheer has expertise in:
• Higher order chromatin architecture
• Nuclear organisation
• Cell and molecular biology
• Cancer genetics and epigenetics
• Molecular pathology of paediatric brain tumours

Teaching

Research

Research Interests:

• Molecular pathology of brain tumours
• Cancer genetics and epigenetics
• Protein aggregation in neurodegeneration
• Chromatin and nuclear organisation
• Cell and molecular biology

Recent and ongoing research projects

Molecular pathology of brain tumours

Low-grade gliomas are the most common form of primary brain tumours in children. Pilocytic astrocytomas (grade I) constitute the largest group of paediatric low-grade gliomas, while grade II gliomas include a diverse group of diffusely infiltrating tumours. Although it is now established that the MAPK signalling pathway is activated in most low-grade gliomas, the detailed molecular mechanisms that determine the varied tumour growth patterns are unknown. Furthermore, the cellular and molecular responses of the tumours to targeted drug therapy are not well-understood.

Our laboratory is conducting a detailed genetic, epigenetic and investigation of the molecular drivers of paediatric low-grade gliomas and the responses to targeted therapy. Following our identification of critical RAF gene alterations that activate the MAPK pathway, we found significant enrichment of sequence microhomology at the breakpoints of BRAF fusions. This discovery provided insights into the probable mechanisms that give rise to these genetic abnormalities. Other investigations led to the novel finding of MYB gene abnormalities in a subset of paediatric low-grade gliomas. In addition, we found that microRNAs overexpressed in pilocytic astrocytomas target the MAPK and NFkB pathways, and we also identified a distinct DNA hypomethylation signature at a set of enhancers in pilocytic astrocytomas.  We are now part of The Everest Centre for Paediatric Low-Grade Brain Tumours, which is formed from a collaboration between the German Cancer Research Centre (DKFZ) in Heidelberg, and Great Ormond Street Hospital/UCL Institute of Child Health and our lab in London - http://bit.ly/EvTBTC.  The aims of the  Everest Centre are: to investigate genomics and cellular origins of these tumours, develop new models for testing new treatments, investigate how the tumours interact with the immune system, and accelerate new clinical trials including the first ever trial into quality of life for patients with low-grade brain tumours.

Protein aggregation in neurodegeneration

Aggregation of misfolded proteins is involved in neurodegenerative and other diseases, but the development of appropriately targeted therapy has been hampered by a complete lack of information on how protein aggregation arises. From a study of how proteins are maintained in a soluble state, we have identified a molecular mechanism that causes protein aggregation and are working to apply this research to the development of novel therapeutics.

Research Group

• Lewis Woodward

Publications

Recent publications

Noor DAM, Jeyapalan JN, Alhazmi S, Carr M, Squibb B, Wallace C, Tan C, Cusack M, Hughes J, Reader T,  Shipley J, Sheer D,  Scotting PJ (2016) Genome-wide methylation analysis identifies genes silenced in non-seminoma cell lines. Npj Genomic Medicine 1:15009

Coll-Bastus N, Mao X, Young BD, Sheer D, Lu YJ (2014) DNA replication-dependent induction of gene proximity by androgen. Human Molecular Genetics.24(4):963-71

Ottaviani D, LeCain M, Sheer D (2014) The role of microhomology in genomic structural variation. Trends in Genetics. 30(3):85-94

Forshew T, Lewis P, Waldman A, Peterson D, Glaser M, Brock C, Sheer D, Mulholland PJ (2013) Three different brain tumours evolving from a common origin. Oncogenesis 2:e41.

Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B, Orisme W, Punchihewa C, Parker M, Qaddoumi I, Boop FA, Lu C, Kandoth C, Ding L, Lee R, Huether R, Chen X, Hedlund E, Nagahawatte P, Rusch M, Boggs K, Cheng J, Becksfort J, Ma J, Song G, Li Y, Wei L, Wang J, Shurtleff S, Easton J, Zhao D, Fulton RS, Fulton LL, Dooling DJ, Vadodaria B, Mulder HL, Tang C, Ochoa K, Mullighan CG, Gajjar A, Kriwacki R, Sheer D, Gilbertson RJ, Mardis ER, Wilson RK, Downing JR, Baker SJ, Ellison DW. (2013) Whole genome sequencing identified genetic alterations in pediatric low- grade gliomas. Nat Genet.  45(6):602-12

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 (2013) Comparative Expression Analysis Reveals Lineage Relationships between Human and Murine Gliomas and a Dominance of Glial Signatures during Tumor Propagation In Vitro. Cancer Research 73(18):5834-44.

Ogunkolade BW, Jones TA, Aarum J, Szary J, Owen N, Ottaviani D, Mumin MA, Patel S, Pieri CA, Silver AR, Sheer D (2013) BORIS/CTCFL is an RNA-binding protein that associates with polysomes. BMC Cell Biol.14:52

Ottaviani D, Lever E, Mao S, Christova R, Ogunkolade BW, Jones TA, Szary J, Aarum J, Mumin MA, Pieri CA, Krawetz SA, Sheer D. (2012) CTCF binds to sites in the major histocompatibility complex that are rapidly reconfigured in response to interferon-gamma. Nucleic Acids Research, 40(12):5262-70

Jones TA, Ogunkolade BW, Szary J, Aarum J, Mumin MA, Patel S, Pieri CA, Sheer D (2011) Widespread expression of BORIS/CTCFL in normal and cancer cells. PLoS ONE 6(7):e22399.

Lawson AR, Hindley GF, Forshew T, Tatevossian RG, Jamie GA, Kelly GP, Neale GA, Ma J, Jones TA, Ellison DW, Sheer D. (2011) RAF gene fusion breakpoints in pediatric brain tumors are characterized by significant enrichment of sequence microhomology. Genome Research 21(4):505-14.

Tatevossian RG, Lawson AR, Forshew T, Hindley GF, Ellison DW, Sheer D. (2010) MAPK pathway activation and the origins of pediatric low-grade astrocytomas. J Cell Physiol. 222(3): 509-14.

Tatevossian RG, Tang B, Dalton J, Forshew T, Lawson AR, Ma J, Neale G, Shurtleff SA, Bailey S, Gajjar A, Baker SJ Sheer D, Ellison DW (2010) MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas. Acta Neuropathol;120(6):731-43.

Reynolds LE, Watson AR, Baker M, Jones TA, D’Amico G, Robinson SD, Joffre C, Garrido-Urbani S, Rodriguez-Manzaneque JC, Martino-Echarri E, Aurrand-Lions M, Sheer D, Dagna-Bricarelli F, Nizetic D, McCabe CJ, Turnell AS, Kermorgant S, Imhof BA, Adams R, Fisher EM, Tybulewicz VL, Hart IR, Hodivala-Dilke KM (2010) Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome. Nature 465(7299):813-817

Lawson AR, Tatevossian RG, Phipps KP, Picker SR, Michalski A, Sheer D, Jacques TS, Forshew T. (2010) RAF gene fusions are specific to pilocytic astrocytoma in a broad paediatric brain tumour cohort. Acta Neuropathol.120(2):271-3.

Lever E, Sheer D. (2010) The role of nuclear organization in cancer. J Pathol. 220(2): 114-25.

Forshew T, Tatevossian RG, Lawson AR, Ma J, Neale G, Ogunkolade BW, Jones TA, Aarum J, Dalton J, Bailey S, Chaplin T, Carter RL, Gajjar A, Broniscer A, Young BD, Ellison DW, Sheer D (2009) Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol. 218(2):172-81.

Ottaviani D, Lever E, Mitter R, Jones T, Forshew T, Christova R, Tomazou, Rakyan VK, Krawetz SA, Platts AE, Segarane B, Beck S, Sheer D (2008) Reconfiguration of genomic anchors upon transcriptional activation of the human MHC. Genome Research 18: 1778-1786.

Christova R, Jones TA, Bolzer A, Wu PJ, Costa-Pereira AP, Watling D, Kerr IM, Sheer D. (2007) P-STAT1 mediates higher order chromatin remodelling of the human Major Histocompatibility Complex in response to IFN-. J Cell Sci 20(18):3262-3270.

Wang J, Shiels C, Sasieni P, Wu PJ, Islam SA, Freemont PS, Sheer D. (2004) Promyelocytic leukemia nuclear bodies associate with transcriptionally active genomic regions. J Cell Biol. 164(4):515-526.

Shiels C, Islam SA, Vatcheva R, Sasieni P, Sternberg MJE, Freemont PS, Sheer D.  (2001) PML bodies associate with the MHC gene cluster. J Cell Sci. 114 (20): 3705-3716.

Volpi EV, Chevret E, Jones T, Vatcheva R, Williamson J, Beck S, Campbell RD, Goldsworthy M, Powis SH, Ragoussis J, Trowsdale J, Sheer D. (2000) Large-scale chromatin organization of the major histocompatibility complex and other regions of human chromosome 6 and its response to interferon in interphase nuclei. J Cell Sci. 113:1565-1576.

Roylance R, Gorman P, Harris W, Liebmann R, Barnes D, Hanby A, Sheer D.  (1999) Comparative genomic hybridization of breast tumors stratified by histological grade reveals new insights into the biological progression of breast cancer. Cancer Res 59:1433-6.

View all Denise Sheer's Research Publications at: http://www.researchpublications.qmul.ac.uk

Supervision

Primary

• Lewis Woodward

Secondary

• Sara Lucchini
• Niamh Baker
• Myrianni Constantinou

Grants

Research in the lab is funded by:

• The Brain Tumour Charity - https://www.thebraintumourcharity.org/
• Rosetrees Trust - http://www.rosetreestrust.co.uk/
• Barts Charity - https://bartscharity.org.uk/
• Queen Mary Innovation - http://www.qminnovation.co.uk/