Plenary Lectures
- Targeting the ubiquitin system for anti-cancer therapy
– Professor Benedikt M Kessler - Modeling human brain development and developmental diseases using hiPSC-derived organoids
– Professor Guo-li Ming - Recognizing sugars: a structural and genomic view of receptors for cell surface glycans
– Professor Kurt Drickamer
Targeting the ubiquitin system for anti-cancer therapy
Professor Benedikt M Kessler
Nuffield Department of Medicine
University of Oxford
Benedikt Kessler graduated from the Swiss Federal Institute of Technology ETH in Zurich, Switzerland in Biochemistry in 1992. He received his PhD in Immunology at the Ludwig Institute for Cancer Research at the University of Lausanne in 1998. He then joined the laboratory of Hidde L. Ploegh at Harvard Medical School in Boston, USA, to study the role of proteolysis in antigen processing and presentation. After three years, he established a research platform in proteomics at HMS. He has then been called to the University of Oxford in the UK, where he currently holds a Professorship in Biochemistry and Life Science Mass Spectrometry at the Target Discovery Institute (TDI). The Kessler group is focused on ubiquitin and protease biology with a specialty in mass spectrometry, proteomics and recently in metabolomics. Expertise in his laboratory is also used to define “molecular signatures” in disease processes and accelerate target discovery in translational research. Benedikt is part of the “DUB Alliance”, a consortium formed by Cancer Research Technologies, Forma Therapeutics and five EU/UK based research groups focused on developing novel drugs against deubiquitylating enzymes (DUBs) for the treatment of cancer.
Website: http://www.tdi.ox.ac.uk/benedikt-kessler
Group home webpage: http://www.tdi.ox.ac.uk/mass-spectometry
Abstract
Ubiquitination controls the stability of most cellular proteins and its deregulation contributes to human diseases. For example, many oncoproteins are subject to ubiquitination-dependent degradation, which is compromised in cancer cells. Deubiquitinases (DUBs) remove ubiquitin from proteins and their inhibition can induce degradation of specific proteins including potentially otherwise undruggable oncoproteins, making DUBs attractive anti-cancer drug targets [1]. Ubiquitin specific protease 7 (USP7) represents a high priority target as USP7 controls the stability of the oncogenic E3 ligase, MDM2, which is reflected in changes to its substrate, the tumour suppressor p53. Inhibition of USP7 leads to degradation of MDM2 coupled to re-activation of p53 in various cancers. We describe the first-in-class highly selective USP7 inhibitors, providing a proof-of-principle example that specific DUB inhibitors can be generated. Our inhibitors show compound-dependent modulation of established USP7 targets including MDM2/p53 in cell culture systems and tumour growth retardation in a MM.1S multiple myeloma xenograft mouse model.
Modeling human brain development and developmental diseases using hiPSC-derived organoids
Professor Guo-li Ming
Perelman School of Medicine
University of Pennsylvania
Dr. Guo-li Ming is currently a Professor of Neuroscience and a member of Institute of Regenerative Medicine at University of Pennsylvania Perelman School of Medicine. She received her medical training on Child and Maternal Care from Tongji Medical University in China in 1994 and Ph.D. from University of California, San Diego in 2002. After her postdoctoral training at the Salk Institute for Biological Studies, she became an Assistant Professor at Johns Hopkins University in 2003 and Professor in 2011. The research in her laboratory centers on understanding the molecular mechanisms underlying neuronal development and its dysregulation using mouse systems and patient derived induced pluripotent stem cells. She has received a number of awards, including Charles E. Culpeper Scholarship in Medical Science in 2003, Alfred P. Sloan Research Fellow in 2005, Young investigator award from Society for Neuroscience in 2012 and A. E. Bennett Research Award from Society of Biological Psychiatry in 2014. She is a member of Society for Neuroscience and American College of Neuropsychopharmacology.
Abstract
Three dimensional (3D) cerebral organoid cultures from human iPSCs have been recently developed to recapitulate the cytoarchitecture of the developing brain. This system offers unique advantages in understanding molecular and cellular mechanisms governing embryonic neural development and in modeling congenital neurodevelopmental disorders, such as microcephaly. We have improved the organoid technology and developed a protocol to produce forebrain-specific organoids derived from human iPSCs using a novel miniaturized spinning bioreactor that recapitulate the human embryonic cortical development. ZIKV, a mosquito-borne flavivirus, has re-emerged as a major public health concern globally because ZIKV causes congenital defects, including microcephaly, and is also associated with Guillain-Barré syndrome in infected adults. We found that ZIKV exhibit specific tropism towards human neural progenitor cells and results in cell death and defects in neural development. I will discuss our recent work in further dissecting the molecular mechanisms underlying the ZIKV pathogenesis and microcephaly.
Recognizing sugars: a structural and genomic view of receptors for cell surface glycans
Professor Kurt Drickamer
Department of Life Sciences
Imperial College London
Kurt Drickamer is Professor of Biochemistry in the Department of Life Sciences at Imperial College London. He obtained his BS degree in chemistry from Stanford University and his PhD in biochemistry and molecular biology from Harvard University. He did postdoctoral work with Professor Robert L. Hill at Duke University and Dr James D. Watson at Cold Spring Harbor Laboratory. He served on the faculty at the University of Chicago, Columbia University, and Oxford University before taking up his present position at Imperial College.
Professor Drickamer has been researching and teaching in biochemistry and glycobiology for more than 35 years. Professor Drickamer's major contribution to the field of glycobiology has been to establish the principle that sugar-binding receptors contain modular carbohydrate-recognition domains that fall into distinct structural groups. His work defined the largest group of receptors, the C-type lectins. His extensive molecular analysis of the C-type lectins has provided detailed explanations for how domains with a common basic framework bind to diverse sugar ligands on cell surfaces and secreted proteins. He has also shown how the binding is tailored to different biological functions. This work allows us to understand how glycan-binding receptors target specific glycoproteins for uptake and degradation, how they facilitate communication between cells and how they lead to identification of pathogen surfaces in the innate immune system.
In recognition of his pioneering work in defining glycan-binding receptors, Professor Drickamer was awarded the Karl Meyer Award of the Society for Glycobiology in 2012 and the International Glycoconjugate Organization Award in 2013. With Dr Maureen Taylor, he worked to create a conceptual framework for understanding the roles of sugars in biology, by authoring the first textbook on glycobiology aimed at a general audience, making the emerging principles in the field accessible to students and the broader scientific community. The book, Introduction to Glycobiology, published by Oxford University Press, is in its 3rd edition and has been translated into Chinese, Japanese and Korean.
Abstract
Receptors that recognise specific sugars mediate cell-cell adhesion and signalling, movements of glycoproteins, and innate immunity. We aim to define the full complement of mammalian glycan-binding receptors and understand how they function. Our biochemical, structural, genomic and glycan-array studies have revealed multiple different mechanisms by which receptors bind selectively to different types of glycans. Receptors found on macrophages, dendritic cells and endothelial cells in the innate immune system favour interaction with broad classes of sugar structures found on the surfaces of viral, bacterial and fungal pathogens. Receptors that mediate cell-cell communication and glycoprotein trafficking utilise more restrictive binding sites that often interact with very specific oligosaccharides. Investigation of these receptors allows us to propose new roles for carbohydrate-mediated communication between cells and to target them for therapeutic purposes.
