Dataset Information

Sialyl Lewis^x-P-selectin cascade mediates tumor-mesothelial adhesion in ascitic fluid shear flow.

ABSTRACT: Organ-specific colonization suggests that specific cell-cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewis^x (sLe^x) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLe^x synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLe^x-P-selectin cascade.

SUBMITTER: Li SS

PROVIDER: S-EPMC6547673 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Sialyl Lewis<sup>x</sup>-P-selectin cascade mediates tumor-mesothelial adhesion in ascitic fluid shear flow.

Li Shan-Shan SS Ip Carman K M CKM Tang Matthew Y H MYH Tang Maggie K S MKS Tong Yin Y Zhang Jiangwen J Hassan Ayon Ahmed AA Mak Abby S C ASC Yung Susan S Chan Tak-Mao TM Ip Philip P PP Lee Cheuk Lun CL Chiu Philip C N PCN Lee Leo Tsz On LTO Lai Hung-Cheng HC Zeng Jin-Zhang JZ Shum Ho Cheung HC Wong Alice S T AST

Nature communications 20190603 1

Organ-specific colonization suggests that specific cell-cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mes ...[more]

PMID: 31160622

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Project description:BackgroundDuring inflammation, leukocytes are captured by the selectin family of adhesion receptors lining blood vessels to facilitate exit from the bloodstream. E-selectin is upregulated on stimulated endothelial cells and binds to several ligands on the surface of leukocytes. Selectin:ligand interactions are mediated in part by the interaction between the lectin domain and Sialyl-Lewis x (sLe(x)), a tetrasaccharide common to selectin ligands. There is a high degree of homology between selectins of various species: about 72 and 60 % in the lectin and EGF domains, respectively. In this study, molecular dynamics, docking, and steered molecular dynamics simulations were used to compare the binding and dissociation mechanisms of sLe(x) with mouse and human E-selectin. First, a mouse E-selectin homology model was generated using the human E-selectin crystal structure as a template.ResultsMouse E-selectin was found to have a greater interdomain angle, which has been previously shown to correlate with stronger binding among selectins. sLe(x) was docked onto human and mouse E-selectin, and the mouse complex was found to have a higher free energy of binding and a lower dissociation constant, suggesting stronger binding. The mouse complex had higher flexibility in a few key residues. Finally, steered molecular dynamics was used to dissociate the complexes at force loading rates of 2000-5000 pm/ps(2). The mouse complex took longer to dissociate at every force loading rate and the difference was statistically significant at 3000 pm/ps(2). When sLe(x)-coated microspheres were perfused through microtubes coated with human or mouse E-selectin, the particles rolled more slowly on mouse E-selectin.ConclusionsBoth molecular dynamics simulations and microsphere adhesion experiments show that mouse E-selectin protein binds more strongly to sialyl Lewis x ligand than human E-selectin. This difference was explained by a greater interdomain angle for mouse E-selectin, and greater flexibility in key residues. Future work could introduce similar amino acid substitutions into the human E-selectin sequence to further modulate adhesion behavior.

Dataset Information

Sialyl Lewis^x-P-selectin cascade mediates tumor-mesothelial adhesion in ascitic fluid shear flow.

Publications

Sialyl Lewis<sup>x</sup>-P-selectin cascade mediates tumor-mesothelial adhesion in ascitic fluid shear flow.

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Dataset Information

Sialyl Lewisx-P-selectin cascade mediates tumor-mesothelial adhesion in ascitic fluid shear flow.

Publications

Sialyl Lewis<sup>x</sup>-P-selectin cascade mediates tumor-mesothelial adhesion in ascitic fluid shear flow.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Sialyl Lewis^x-P-selectin cascade mediates tumor-mesothelial adhesion in ascitic fluid shear flow.