Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways

Cécile Cumin¹, Yen-Lin Huang², Charlotte Rossdam³, Felix Ruoff⁴, Susana Posada Céspedes⁵, Ching-Yeu Liang², Flavio C Lombardo², Ricardo Coelho², Natalie Rimmer², Martina Konantz⁶, Mónica Núñez López², Shahidul Alam⁷, Alexander Schmidt⁸, Diego Calabrese², Andre Fedier², Tatjana Vlajnic⁹, Mark von Itzstein¹⁰, Markus Templin⁴, Falk F R Buettner³, Arun Everest-Dass¹¹, Viola Heinzelmann-Schwarz¹², Francis Jacob¹³

Affiliations

¹ Ovarian Cancer Research, University Hospital Basel and University of Basel, Basel, Switzerland; Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.
² Ovarian Cancer Research, University Hospital Basel and University of Basel, Basel, Switzerland.
³ Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
⁴ NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
⁵ Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
⁶ Stem Cells and Hematopoiesis, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
⁷ Centre for Organismal Studies, Heidelberg Universität, Heidelberg, Germany.
⁸ Biozentrum University of Basel, Basel, Switzerland.
⁹ Institute of Pathology, Kantonsspital Graubünden, Chur, Switzerland.
¹⁰ Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.
¹¹ Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia. Electronic address: a.everest-dass@griffith.edu.au.
¹² Ovarian Cancer Research, University Hospital Basel and University of Basel, Basel, Switzerland; Department of Gynecology and Gynecological Oncology, Hospital for Women, University Hospital Basel, Switzerland.
¹³ Ovarian Cancer Research, University Hospital Basel and University of Basel, Basel, Switzerland. Electronic address: francis.jacob@unibas.ch.

PMID: 35977490
DOI: 10.1016/j.celrep.2022.111181

Free article

Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways

Cécile Cumin et al. Cell Rep. 2022.

Free article

. 2022 Aug 16;40(7):111181.

doi: 10.1016/j.celrep.2022.111181.

Authors

Affiliations

¹ Ovarian Cancer Research, University Hospital Basel and University of Basel, Basel, Switzerland; Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.
² Ovarian Cancer Research, University Hospital Basel and University of Basel, Basel, Switzerland.
³ Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
⁴ NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
⁵ Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
⁶ Stem Cells and Hematopoiesis, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
⁷ Centre for Organismal Studies, Heidelberg Universität, Heidelberg, Germany.
⁸ Biozentrum University of Basel, Basel, Switzerland.
⁹ Institute of Pathology, Kantonsspital Graubünden, Chur, Switzerland.
¹⁰ Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.
¹¹ Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia. Electronic address: a.everest-dass@griffith.edu.au.
¹² Ovarian Cancer Research, University Hospital Basel and University of Basel, Basel, Switzerland; Department of Gynecology and Gynecological Oncology, Hospital for Women, University Hospital Basel, Switzerland.
¹³ Ovarian Cancer Research, University Hospital Basel and University of Basel, Basel, Switzerland. Electronic address: francis.jacob@unibas.ch.

PMID: 35977490
DOI: 10.1016/j.celrep.2022.111181

Abstract

The molecular repertoire promoting cancer cell plasticity is not fully elucidated. Here, we propose that glycosphingolipids (GSLs), specifically the globo and ganglio series, correlate and promote the transition between epithelial and mesenchymal cells. The epithelial character of ovarian cancer remains stable throughout disease progression, and spatial glycosphingolipidomics reveals elevated globosides in the tumor compartment compared with the ganglioside-rich stroma. CRISPR-Cas9 knockin mediated truncation of endogenous E-cadherin induces epithelial-to-mesenchymal transition (EMT) and decreases globosides. The transcriptomics analysis identifies the ganglioside-synthesizing enzyme ST8SIA1 to be consistently elevated in mesenchymal-like samples, predicting poor outcome. Subsequent deletion of ST8SIA1 induces epithelial cell features through mTOR^S2448 phosphorylation, whereas loss of globosides in ΔA4GALT cells, resulting in EMT, is accompanied by increased ERK^Y202/T204 and AKT^S124. The GSL composition dynamics corroborate cancer cell plasticity, and further evidence suggests that mesenchymal cells are maintained through ganglioside-dependent, calcium-mediated mechanisms.

Keywords: CP: Cancer; EMT; MALDI imaging; MET; calcium; gangliosides; globosides; ovarian cancer; sialic acid; signaling pathways.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways

Affiliations

Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways

Authors

Affiliations

Abstract

Conflict of interest statement

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MeSH terms

Substances

LinkOut - more resources

Full Text Sources