GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior

Abstract

While better management of loco-regional prostate cancer (PC) has greatly improved survival, advanced PC remains a major cause of cancer deaths. Novel, targetable, pathways that contribute to tumorigenesis in advanced PC could open new therapeutic options. The di-ganglioside GD2 is a target of FDA-approved antibody therapies in neuroblastoma, but any role of GD2 in PC is little explored. Here, we show that GD2 is expressed on a small subpopulation of tumor cells in a subset of PC patients, especially in metastatic PC. Variable levels of cell surface GD2 expression are seen in most PC cell lines, and the expression is highly upregulated by experimental induction of lineage progression or enzalutamide resistance in CRPC cell models. GD2+ fraction is enriched upon growth of PC cells as tumorspheres and GD2+ fraction is enriched in tumorsphere growth. CRISPR-Cas9 knockout (KO) of the rate-limiting GD2 biosynthetic enzyme GD3 Synthase (GD3S) in GD2-high CRPC cell models led to marked impairment of their in vitro oncogenic traits, reduced cancer stem cell and epithelial-mesenchymal transition marker expression and growth as bone-implanted xenograft tumors. Our results support a potential role of GD3S and its product GD2 in promoting PC tumorigenesis, likely by its recently demonstrated role in maintaining cancer stem cells and suggest the potential for GD2 targeting in advanced PC.