Testicular germ cell tumors (GCTs) are stratified into seminomas and non-seminomas. Seminomas share many histological and molecular features with primordial germ cells, whereas the non-seminoma stem cell population - embryonal carcinoma (EC) - is pluripotent and thus able to differentiate into cells of all three germ layers (teratomas). Furthermore, ECs are capable of differentiating into extra-embryonic lineages (yolk-sac tumors, choriocarcinomas). In this study, we deciphered the molecular and (epi)genetic mechanisms regulating expression of CD24, a highly glycosylated signaling molecule upregulated in many cancers. CD24 is overexpressed in ECs compared to other GCT entities and can be associated with an undifferentiated pluripotent cell fate. We demonstrate that CD24 can be transactivated by the pluripotency factor SOX2, which binds in proximity to the CD24 promoter. In GCTs, CD24 expression is controlled by epigenetic mechanisms, i.e. histone acetylation, since CD24 can be induced by the application histone deacetylase inhibitors. Vice versa, CD24 expression is downregulated upon inhibition of histone methyltransferases, E3-ubiquitin ligases or bromodomain (BRD) proteins. Additionally, three-dimensional (3D) co-cultivation of EC cells with microenvironmental cells, such as fibroblasts, endothelial or immune cells, reduced CD24 expression, suggesting that crosstalk with the somatic microenvironment influences CD24 expression. In a CRISPR/Cas9-deficiency model, we demonstrate that CD24 fulfils a bivalent role in differentiation via regulation of homeobox, phospho- and glycoproteins, i.e. it is involved in suppressing the germ cell/spermatogenesis program and mesodermal/endodermal differentiation, while poising the cells for ectodermal differentiation. Finally, blocking CD24 by a monoclonal antibody enhanced sensitivity towards cisplatin in EC cells, including cisplatin-resistant subclones, highlighting CD24 as a putative target in combination with cisplatin.
Molecular oncology. 2021 Jul 22 [Epub ahead of print]
Margaretha A Skowron, Teresa K Becker, Lukas Kurz, Sina Jostes, Felix Bremmer, Florian Fronhoffs, Kai Funke, Gamal A Wakileh, Melanie R Müller, Aaron Burmeister, Thomas Lenz, Anja Stefanski, Kai Stühler, Patrick Petzsch, Karl Köhrer, Peter Altevogt, Peter Albers, Glen Kristiansen, Hubert Schorle, Daniel Nettersheim
Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany., Department of Oncological Science, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, USA., Institute of Pathology, University Medical Center Goettingen, Goettingen, Germany., Institute of Pathology, University Hospital Bonn, Bonn, Germany., Department of Developmental Pathology, Institute of Pathology, University Hospital Bonn, Bonn, Germany., Molecular Proteomics Laboratory, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany., Genomics & Transcriptomics Lab, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Skin Cancer Unit, German Cancer Research Center (DKFZ), Germany., Department of Urology, University Hospital Düsseldorf, Düsseldorf, Germany.