Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways

The molecular repertoire promoting cancer cell plasticity is not fully elucidated. Here, we propose that glyco-sphingolipids (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 compart-ment 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 mTORS2448 phosphorylation, whereas loss of globosides in DA4GALT cells, resulting in EMT, is accompanied by increased ERKY202/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.

Automated summary

The molecular repertoire promoting cancer cell plasticity remains partly unknown, but this study proposes that glyco-sphingolipids, specifically globo and ganglio series, play a role in promoting the transition between epithelial and mesenchymal cells. The study found elevated levels of globosides in tumor compartments compared to the ganglioside-rich stroma. It also discovered that the ganglioside-synthesizing enzyme ST8SIA1 was consistently elevated in mesenchymal-like samples, indicating a poor outcome.