Distinct kinetic and mechanical properties govern mucin 16- and podocalyxin-mediated tumor cell adhesion to E- and L-selectin in shear flow

Oncotarget
Daniel J SheaKonstantinos Konstantopoulos

Abstract

Selectin-mediated tumor cell tethering to host cells, such as vascular endothelial cells, is a critical step in the process of cancer metastasis. We recently identified sialofucosylated mucin16 (MUC16) and podocalyxin (PODXL) as the major functional E- and L-selectin ligands expressed on the surface of metastatic pancreatic cancer cells. While the biophysics of leukocyte binding to selectins has been well studied, little is known about the mechanics of selectin-mediated adhesion pertinent to cancer metastasis. We thus sought to evaluate the critical parameters of selectin-mediated pancreatic tumor cell tethering and rolling. Using force spectroscopy, we characterized the binding interactions of MUC16 and PODXL to E- and L-selectin at the single-molecule level. To further analyze the response of these molecular interactions under physiologically relevant regimes, we used a microfluidic assay in conjunction with a mathematical model to study the biophysics of selectin-ligand binding as a function of fluid shear stress. We demonstrate that both MUC16 and PODXL-E-selectin-mediated interactions are mechanically stronger than like L-selectin interactions at the single-molecule level, and display a higher binding frequency at all cont...Continue Reading

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Citations

Apr 25, 2017·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Anna JablonskaPiotr Walczak
Aug 3, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Daniel J SheaKonstantinos Konstantopoulos
Nov 12, 2018·Cell Systems·Erin Elizabeth EdwardsSusan Napier Thomas

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Methods Mentioned

BETA
glycosylation
flow cytometry
gel filtration

Software Mentioned

Igor Pro
BD CellQuest Pro
image J

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