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A. Natoni et al.
soned that global suppression of sialylation could have effects beyond E-selectin. Indeed, 3Fax-Neu5Ac induced a general reduction in the motility of treated cells. This prompted us to investigate whether desialylation would alter adhesion and rolling mediated by α4β7 and α4β1 integrins, which are highly expressed on MM cells.41-44 In a shear stress adhesion assay, we observed that 3Fax-Neu5Ac reduced the number of adherent cells on VCAM1 and, sur- prisingly, adhesion on MADCAM1. MADCAM1 is an immunoglobulin superfamily adhesion molecule expressed by mucosal venules that helps direct lympho- cyte trafficking into Peyer's patches and the intestinal lam- ina propria.29,45 There is also evidence that interaction between HSC and endothelial MADCAM1 in the BM pro- motes the homing and engraftment of HSC in mice.46-48 In a similar way, MADCAM1 could co-operate with SDF1α and E-selectin to facilitate homing of MM cell in the BM. Indeed, MADCAM1 ligand α4/β7 has been shown to play a critical role in MM-cell adhesion, migration, invasion, BM homing, and adhesion-mediated drug resistance.43,49 Moreover, it was shown that the expression levels of β7 integrin on MM cells correlates with poor survival in MM patients.43 Our results suggest the possibility of reduced interactions between endothelial MADCAM1 and α4/β7 on MM cells as a result of desialylation. Indeed, we showed that 3Fax-Neu5Ac altered the SDS-PAGE mobility of the α4 chain and in particular of its mature forms, sug- gesting that desialylation interferes with α4 maturation. The interaction between MM cells and MADCAM1 becomes apparent only under shear stress as we failed to
detect adhesion on MADCAM1 under static conditions (data not shown). This is highly reminiscent of L-selectin on leukocytes that requires a threshold shear stress to establish rolling and adhesion, below which no interactions are observed.50 Thus, it is possible that MAD- CAM1 mediates or facilitates homing but not retention of the MM cells in the BM.
In conclusion, targeting sialylation in MM cells has the potential to block the ability of MM cells to home to the BM, which, in turn, could reduce the severity of the disease, because most existing therapies against MM, like borte- zomib, are maximally effective on circulating MM cells.
Funding
The authors would like to acknowledge the Health Research Board (CSA 2012/10) and NIH’s National Institute of General Medical Sciences (NIH P30 GM106391, P30GM103392, P20GM121301, and U54GM115516) for funding this work.
The authors’ work is also supported by start-up funds from the Maine Medical Center Research Institute, a pilot awarded to Dr. Reagan and core facilities from the Massachusetts General Hospital Center for Skeletal Research (NIH/NIAMS P30AR066261), and a pilot grant from the American Cancer Society (Research Grant #IRG-16-191-33; Reagan PI).
Acknowledgments
The authors would also like to acknowledge the Flow Cytometry Core Facility at NUI Galway. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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