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MSL Faculty Candidate Seminar: Dr. Simon Wisnovsky
February 12, 2020 @ 10:00 am - 11:00 am
The Michael Smith Laboratories presents a faculty candidate seminar:
Dr. Simon Wisnovsky
Department of Chemistry
Date: Wednesday, February 12th
Time: 9:00 AM
Location: MSL Auditorium (MSL 102) – 2185 East Mall
Title: Translating the Cancer Glyco-Code with Chemical-Genetic Screening
Abstract: All cells attach chains of sugar molecules (called glycans) to cell-surface proteins and lipids, generating the complex chemical language of the cellular glyco-code. During cancer development, this glyco-code is extensively rewritten through increased biosynthesis of glycans containing the sialic acid monosaccharide. These diverse oligosaccharide structures act as ligands for the Siglec (Sialic Acid-Binding IgG-Like Lectin) family of receptors widely expressed on immune cells. Binding of Siglecs to cancer-associated glycans suppresses immune cell activation, allowing tumour cells to escape immune surveillance. Disruption of this immunoregulatory axis could represent a potent therapeutic strategy for enhancing the anticancer immune response. Siglec binding, however, is mediated by multivalent interactions with chemically complex, heterogenous glycoprotein elements. Such functional interfaces have thus been difficult to characterize using traditional biochemical techniques. I will discuss a novel chemical-genetics approach to defining the composition and linkage structure of Siglec-binding antigens. CRISPR genomic screening technology was used to generate a global map of genes whose knockout abolishes Siglec binding to the surface of cancer cells. Most significantly, these studies revealed a novel, unexpectedly selective interaction between Siglec-7 and a single cell-surface glycoprotein that acts as a professional ligand for this receptor. Chemical analysis of this glycoprotein with mass spectrometry-based glycoproteomics lead to the identification of a novel glycopeptide motif that forms a high-affinity Siglec-7 binding domain. Blockade of this domain with a targeted antibody robustly enhances immune killing of leukemia cells, a finding with immediate implications for the development of novel cancer immunotherapies. The genomic screening approach outlined here represents a general strategy for characterization of glycoprotein-receptor interactions with broad applicability to the study of glycoscience in disease.