While altered glycosylation patterns have long been identified as hallmarks of cancer, their functional significance with respect to tumor progression are not well understood. Two examples are overexpression of mucin glycoproteins (densely glycosylated cell-surface molecules with unusual physical properties) and hypermodification of glycoproteins with the terminal sugar sialic acid. These glycosylation phenotypes are found on numerous cancer types with highly varied underlying driver mutations and their magnitude tends to correlate with tumor aggressiveness. To test hypotheses regarding the functional significance of cancerglycomes, we developed an approach to engineer the cell surface “glycocalyx” with chemically defined glycopolymers that emulate cancer-associated structures. Using living polymerization and chemoselective ligation chemistries, we synthesize glycopolymers functionalized with a biophysical probe on one end and a lipid capable of membrane insertion on the other. These biomimetic structures can be displayed on live cell membranes where they acquire functions analogous to natural mucin glycoproteins. Our work using this platform suggests that hypersialylation protects tumor cells from innate immune surveillance, whereas mucin upregulation alters the physical properties of the glycocalyx so as to promote focal adhesion formation and signaling.  Both glycophenotypes can thus be understood as evolutionary adaptations of cancer cells under various selective pressures.

Why do cancer cells have altered glycosylation?

251st National Meeting (2016)

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