Date/Time Date(s) - 23/01/20201:30 pm - 2:30 pm
Title: Translating theCancer Glyco-Code with Chemical-Genetic Screening
Date: Thursday January 23,2020
Time: 1:30 p.m.
Place: ABB 165
ABSTRACT:
All cells attach chains of sugar molecules (called glycans)to cell-surface proteins and lipids, generating the complex chemical languageof the cellular glyco-code. During cancer development, this glyco-code is extensivelyrewritten through increased biosynthesis of glycans containing the sialic acidmonosaccharide. These diverse oligosaccharide structures act as ligands for theSiglec (Sialic Acid-Binding IgG-Like Lectin) family of receptors widelyexpressed on immune cells. Binding of Siglecs to cancer-associated glycanssuppresses immune cell activation, allowing tumour cells to escape immunesurveillance. Disruption of this immunoregulatory axis could represent a potenttherapeutic strategy for enhancing the anticancer immune response. Siglecbinding, however, is mediated by multivalent interactions with chemicallycomplex, heterogenous glycoprotein elements. Such functional interfaces havethus been difficult to characterize using traditional biochemical techniques.Here, I will discuss a novel chemical-genetics approach to defining thecomposition and linkage structure of Siglec-binding antigens. CRISPR genomicscreening technology was used to generate a global map of genes whose knockoutabolishes Siglec binding to the surface of cancer cells. Most significantly,these studies revealed a novel, unexpectedly selective interaction betweenSiglec-7 and a single cell-surface glycoprotein that acts as a professionalligand for this receptor. Chemical analysis of this glycoprotein with massspectrometry-based glycoproteomics lead to the identification of a novelglycopeptide motif that forms a high-affinity Siglec-7 binding domain. Blockadeof this domain with a targeted antibody robustly enhances immune killing ofleukemia cells, a finding with immediate implications for the development ofnovel cancer immunotherapies. The genomic screening approach outlined hererepresents a general strategy for characterization of glycoprotein-receptorinteractions with broad applicability to the study of glycoscience in disease.