Sialic acid perturbation leads to profound remodeling of glycocalyx architecture and cellular mechanics in pancreatic cancer cells

Authors

• AE Massey
• S Behrman
• G Altan-Bonnet
• AX Cartagena-Rivera

Abstract

Pancreatic cancer remains one of the most lethal malignancies due in part to issues with early detection and high levels of drug resistance. Partly to blame for these is the glycocalyx, an extracellular structure found on most cells that is aberrantly glycosylated and has overexpressed biopolymers in cancerous cells. In pancreatic cancer, this includes higher levels of mucin expression, increased sialylation, and more hyaluronic acid production. Although there is considerable work detailing the biochemical role of these glycocalyx modifications, we sought to understand their role on the architecture and mechanical properties of the cell. We enzymatically degraded different components of the glycocalyx commonly found to be aberrantly expressed in pancreatic cancer (e.g., N-glycans, sialic acid, mucins, and hyaluronic acid) and visualized changes in the structure of the membrane via atomic force microscopy, confocal staining and scanning electron microscopy. We observed a profound reduction in microvilli density that was the most consistent with sialic acid removal across all three cell lines investigated, as well as a significant reduction in the viscoelastic properties (elastic storage and viscous loss moduli) with this treatment. This observation suggests that the cell surface fluidizes in response to desialylation. In addition, preliminary cytokine expression data suggests that sialic acid removal leads to a pronounced immune response, greater than removing other glycocalyx components. Future studies will attempt to link in vitro effects of de-glycosylation with patient tissue viscoelastic data to highlight the role of glycocalyx modulation at an intratumoral level to better understand chemo and immune therapy resistance.

Scientific Focus Area: Biomedical Engineering and Biophysics

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