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Glycosphingolipids in human embryonic stem cells and breast cancer stem cells, and potential cancer therapy strategies based on their structures and functions

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Abstract

Expression profiles of glycosphingolipids (GSLs) in human embryonic stem cell (hESC) lines and their differentiated embryoid body (EB) outgrowth cells, consisting of three germ layers, were surveyed systematically. Several globo- and lacto-series GSLs were identified in undifferentiated hESCs and during differentiation of hESCs to EB outgrowth cells, and core structure switching of these GSLs to gangliosides was observed. Such switching was attributable to altered expression of key glycosyltransferases (GTs) in GSL biosynthetic pathways, reflecting the unique stage-specific transitions and mechanisms characteristic of the differentiation process. Lineage-specific differentiation of hESCs was associated with further GSL alterations. During differentiation of undifferentiated hESCs to neural progenitor cells, core structure switching from globo- and lacto-series to primarily gangliosides (particularly GD3) was again observed. During differentiation to endodermal cells, alterations of GSL profiles were distinct from those in differentiation to EB outgrowth or neural progenitor cells, with high expression of Gb4Cer and low expression of stage-specific embryonic antigen (SSEA)-3, -4, or GD3 in endodermal cells. Again, such profile changes resulted from alterations of key GTs in GSL biosynthetic pathways. Novel glycan structures identified on hESCs and their differentiated counterparts presumably play functional roles in hESCs and related cancer or cancer stem cells, and will be useful as surface biomarkers. We also examined GSL expression profiles in breast cancer stem cells (CSCs), using a model of epithelial-mesenchymal transition (EMT)-induced human breast CSCs. We found that GD2 and GD3, together with their common upstream GTs, GD3 synthase (GD3S) and GD2/GM2 synthase, maintained stem cell phenotype in breast CSCs. Subsequent studies showed that GD3 was associated with epidermal growth factor receptor (EGFR), and activated EGFR signaling in breast CSCs and breast cancer cell lines. GD3S knockdown enhanced cytotoxicity of gefitinib (an EGFR kinase inhibitor) in resistant MDA-MB468 cells, both in vitro and in vivo. Our findings indicate that GD3S contributes to gefitinib resistance in EGFR-positive breast cancer cells, and is a potentially useful therapeutic target in drug-resistant breast cancers.

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Fig. 1

Adapted from Fig. 2 in Ref. [29] and Fig. 3 in ref. [30]

Fig. 2

Adapted from Fig. 1 in Ref. [67]

Fig. 3

Adapted from Fig. 4 & 5 in Ref. [68]

Fig. 4

Adapted from Fig. 7 & 8 in Ref. [68]

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Acknowledgements

These studies were supported by grants from Ministry of Science and Technology (MOST 104-2314-B-182A-048 -MY3; 110-2314-B-075-010-MY3), Taiwan, R.O.C., VGHUST Joint Research Program, Tsou Foundation (VGHUST110-G7-3-3) and from VGHTPE Research Program (V107C-161, V108C-059 and V109C-049). The authors are grateful to all previous coworkers for their contributions, and to Dr. S. Anderson for English editing of the manuscript. Fig. 1 is modified from Proc Natl Acad Sci USA 2010 107: 22564-22569 and Stem Cells 2011 29: 1995-2004. Fig. 2 is reprinted from Proc Natl Acad Sci USA 2013 110: 4968-4973. Figs. 3, 4 are modified from Oncotarget 2017 8(29): 47454- 47473.

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  1. Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, 11217, Taiwan

    Yuh-Jin Liang

  2. Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Yuh-Jin Liang

  3. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Yuh-Jin Liang

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Liang, YJ. Glycosphingolipids in human embryonic stem cells and breast cancer stem cells, and potential cancer therapy strategies based on their structures and functions. Glycoconj J 39, 177–195 (2022). https://doi.org/10.1007/s10719-021-10032-w

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