Cancer cells are frequently characterized by extensive remodeling of their cell surface glycocalyx, the complex pattern of sugar modifications that decorate cell surface proteins. In particular, cancer cells often overexpress an unusually high density of sialic acid glycans on their plasma membrane; this modification shields tumors from detection by the immune system by robustly inhibiting immune activation. In recent years potent cancer immunotherapies, which target tumors by enhancing the native anticancer activity of immune cells, have shown the potential to revolutionize cancer treatment. These advances have made it critical to better understand the mechanisms by which cancers evade immune surveillance. The oncogenic signaling pathways that specifically coordinate upregulation of cell surface sialic acid in cancer, however, remain poorly characterized. This proposal aims to comprehensively identify the genetic drivers of cancer glyocalyx remodeling using a novel chemical-genetic screening strategy. The Bertozzi group has perfected a set of chemical probes that allow for rapid, sensitive visualization of changes in cell surface sialic acid levels using bioorthaganal chemistry. These techniques will be applied to develop a high-throughput, multiplexed platform for quantitating changes in cell surface sialic acid content (Aim 1). siRNA and CRISPR functional genetic techniques will then be used to profile genes whose ablation causes cancer-specific reversal of cell-surface hypersialylation (Aims 1 & 2). These studies will identify a set of signaling molecules with putative roles in driving cancer glyocalyx remodeling that will be evaluated as potential anticancer targets (Aim 3). By combining cutting edge chemical biology and genetic screening techniques, this proposal will be the first study to comprehensively annotate the genetic factors underlying one of the most important emerging hallmarks of cancer, with important implications for development of future immunotherapies.

Public Health Relevance

In order to escape detection by the immune system, cancer cells frequently alter their cell surface glycosylation patterns (termed the glycocalyx) so as to overexpress sugar molecules that inhibit immune cell activation. This research aims to discover the currently uncharacterized genetic factors underlying this oncogenic change through application of a high-throughput genetic screening platform that uses chemical probes to rapidly visualize changes in cell surface glycan modifications. This work will allow for identification of signaling pathways that drive glycocalyx remodeling in cancer and will aid significantly in the development of novel immune-targeted therapies for cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA228540-01
Application #
9539424
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcguirl, Michele
Project Start
2018-09-10
Project End
Budget Start
2018-09-10
Budget End
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304