Development of Mucin-mimetics to Study the Role of the Glycocalyx in Oncogenesis

University Of California Berkeley, Berkeley CA

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Abstract

? DESCRIPTION (provided by applicant): Mucins are upregulated in more than 90% of breast cancers and many other carcinomas, and their link to oncogenesis is clear. Still, the role of their large extracellular domains-a major structural component of the glycocalyx-in this oncogenesis has yet to be elucidated. Because it is known that integrin-mediated adhesion can play a critical role in such diverse cellular processes as differentiation, proliferation, migration and apoptosis, aberrant integrin function has been linked to oncogenesis in myriad ways. Preliminary studies suggest that mucins could play a role in boosting the pro-malignant functions of integrin signaling by changing the physical properties of the glycocalyx. Mucins are heavily O-glycosylated membrane-associated proteins involved in the protection of epithelia from luminal insults. Because they often consist of greater than 50% glycan by mass, their structures are not easily manipulated using standard molecular biology techniques. An approach to studying these molecules relying on synthetic mucin-mimetic glycopolymers has proven a tractable method to overcome this obstacle. Well-defined, polymeric alkane backbones with pendant ketones are easily decorated with aminooxy-glycans. One end of the polymer contains a probe for microscopy and the other a hydrophobic tail for spontaneous insertion into cell membranes. In this proposal we will test the hypothesis that the glycocalyx affects integrin-mediated adhesion in a structure dependent manner, and thus drives a metastatic phenotype, by utilizing these mucin-mimetics. In Specific Aim 1, mucin-mimetic glycopolymers will be improved by increasing their ability to reside on cell surfaces for longer periods of time by chemically modifying their hydrophobic anchors. Increasing cell-surface half-lives will vastly improve these polymers as tools with which to study the glycocalyx and its components. In Specific Aim 2, structural variation of the glycocalyx will be studied using these tools and its effect on integrin- driven metastatic phenotype will be characterized. If confirmed, this hypothesis would present a paradigm shift for the role of the mucins, and the glycocalyx, in oncogenesis.