ABSTRACT
While better management of loco-regional prostate cancer (PC) has greatly improved survival, advanced PC remains a major cause of cancer deaths. Identification of novel targetable pathways that contribute to tumor progression in PC could open new therapeutic options. The di-ganglioside GD2 is a target of FDA-approved antibody therapies in neuroblastoma, but the role of GD2 in PC is unexplored. Here, we show that GD2 is expressed in a small subpopulation of PC cells in a subset of patients and a higher proportion of metastatic tumors. Variable levels of cell surface GD2 expression were seen on many PC cell lines, and the expression was highly upregulated by experimental induction of lineage progression or enzalutamide resistance in CRPC cell models. GD2high cell fraction was enriched upon growth of PC cells as tumorspheres and GD2high fraction was enriched in tumorsphere-forming ability. CRISPR-Cas9 knockout (KO) of the rate-limiting GD2 biosynthetic enzyme GD3 Synthase (GD3S) in GD2high CRPC cell models markedly impaired the in vitro oncogenic traits and growth as bone-implanted xenograft tumors and reduced the cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT) marker expression. Our results support the potential role of GD3S and its product GD2 in promoting PC tumorigenesis by maintaining cancer stem cells and suggest the potential for GD2 targeting in advanced PC.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵* Co-First Authors
Financial support: This research was funded by Pilot grants from the Fred & Pamela Buffett Cancer Center (HB & VB); Department of Defense grants W81XWH-17-1-0616 and W81XWH-20-1-0058 to HB and W81XWH-20-1-0546 to VB; the NIH grants R21CA241055 and R03CA253193 to VB; the NIH Pathway to Independence Award R00 GM1287671 and the NIH MIRA award R35 GM147467 (to M.J.R.); the Raphael Bonita Memorial Fund; and support to UNMC core facilities from the NCI Cancer Center Support Grant (P30CA036727) awarded to Fred & Pamela Buffett Cancer Center and from the Nebraska Research Initiative. AMB, SC and IM received the University of Nebraska Medical Center Graduate Student Fellowships.
Conflict of interest disclosure statement: Dr. H. Band and Dr. V. Band received funding from Nimbus Therapeutics for an unrelated project.
Revised manuscript title, Revised manuscript text, Additional authors and additional data.