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 () and Alice S. T. Wong ()
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Shan-Shan Li: University of Hong Kong
Carman K. M. Ip: University of Hong Kong
Matthew Y. H. Tang: University of Hong Kong
Maggie K. S. Tang: University of Hong Kong
Yin Tong: University of Hong Kong
Jiangwen Zhang: University of Hong Kong
Ayon Ahmed Hassan: University of Hong Kong
Abby S. C. Mak: University of Hong Kong
Susan Yung: University of Hong Kong, Queen Mary Hospital
Tak-Mao Chan: University of Hong Kong, Queen Mary Hospital
Philip P. Ip: University of Hong Kong, Queen Mary Hospital
Cheuk Lun Lee: University of Hong Kong, Queen Mary Hospital
Philip C. N. Chiu: University of Hong Kong, Queen Mary Hospital
Leo Tsz On Lee: Faculty of Health Sciences, University of Macau
Hung-Cheng Lai: Taipei Medical University
Jin-Zhang Zeng: Xiamen University
Ho Cheung Shum: University of Hong Kong
Alice S. T. Wong: University of Hong Kong

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10334-6

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