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

Shan Shan Li, Carman K.M. Ip, Matthew Y.H. Tang, Maggie K.S. Tang, Yin Tong, Jiangwen Zhang, Ayon Ahmed Hassan, Abby S.C. Mak, Susan Yung, Tak Mao Chan, Philip P. Ip, Cheuk Lun Lee, Philip C.N. Chiu, Leo Tsz On Lee, Hung Cheng Lai, Jin Zhang Zeng, Ho Cheung Shum, Alice S.T. Wong

Research output: Contribution to journalArticle

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-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex 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 sLex-P-selectin cascade.

Original languageEnglish
Article number2406
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

Fingerprint

P-Selectin
Cascades (fluid mechanics)
Ascitic Fluid
Shear flow
shear flow
Tumors
cascades
adhesion
tumors
Adhesion
Neoplastic Stem Cells
Fluids
stems
fluids
galactoside 3-fucosyltransferase
cancer
Neoplasms
shear stress
Shear stress
Epithelium

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Li, S. S., Ip, C. K. M., Tang, M. Y. H., Tang, M. K. S., Tong, Y., Zhang, J., ... Wong, A. S. T. (2019). Sialyl Lewisx-P-selectin cascade mediates tumor–mesothelial adhesion in ascitic fluid shear flow. Nature Communications, 10(1), [2406]. https://doi.org/10.1038/s41467-019-10334-6

Sialyl Lewisx-P-selectin cascade mediates tumor–mesothelial adhesion in ascitic fluid shear flow. / Li, Shan Shan; Ip, Carman K.M.; Tang, Matthew Y.H.; Tang, Maggie K.S.; Tong, Yin; Zhang, Jiangwen; Hassan, Ayon Ahmed; Mak, Abby S.C.; Yung, Susan; Chan, Tak Mao; Ip, Philip P.; Lee, Cheuk Lun; Chiu, Philip C.N.; Lee, Leo Tsz On; Lai, Hung Cheng; Zeng, Jin Zhang; Shum, Ho Cheung; Wong, Alice S.T.

In: Nature Communications, Vol. 10, No. 1, 2406, 01.12.2019.

Research output: Contribution to journalArticle

Li, SS, Ip, CKM, Tang, MYH, Tang, MKS, Tong, Y, Zhang, J, Hassan, AA, Mak, ASC, Yung, S, Chan, TM, Ip, PP, Lee, CL, Chiu, PCN, Lee, LTO, Lai, HC, Zeng, JZ, Shum, HC & Wong, AST 2019, 'Sialyl Lewisx-P-selectin cascade mediates tumor–mesothelial adhesion in ascitic fluid shear flow', Nature Communications, vol. 10, no. 1, 2406. https://doi.org/10.1038/s41467-019-10334-6
Li, Shan Shan ; Ip, Carman K.M. ; Tang, Matthew Y.H. ; Tang, Maggie K.S. ; Tong, Yin ; Zhang, Jiangwen ; Hassan, Ayon Ahmed ; Mak, Abby S.C. ; Yung, Susan ; Chan, Tak Mao ; Ip, Philip P. ; Lee, Cheuk Lun ; Chiu, Philip C.N. ; Lee, Leo Tsz On ; Lai, Hung Cheng ; Zeng, Jin Zhang ; Shum, Ho Cheung ; Wong, Alice S.T. / Sialyl Lewisx-P-selectin cascade mediates tumor–mesothelial adhesion in ascitic fluid shear flow. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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N2 - 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-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex 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 sLex-P-selectin cascade.

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