Carbonic Anhydrase XII is a Clinically Significant, Molecular Tumor-Subtype Specific Therapeutic Target in Glioma with the Potential to Combat Invasion of Brain Tumor Cells

Abstract

Guanzhang Li,1,* Ting-Wei Chen,2,* Ann-Christin Nickel,2 Sajjad Muhammad,2 Hans-Jakob Steiger,2 Theophilos Tzaridis,3,4 Daniel Hänggi,2 Reinhard Zeidler,5 Wei Zhang,6– 8 Ulf Dietrich Kahlert1,2 1Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People’s Republic of China; 2Clinic for Neurosurgery, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany; 3Division of Clinical Neurooncology, Department of Neurology and Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, 53127, Germany; 4Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA; 5Department for Otorhinolaryngology, Klinikum der Universität München (LMU), Munich, Germany; 6Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 7China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China; 8Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ulf Dietrich Kahlert Moorenstrasse 5, Düsseldorf, 40225, GermanyTel [phone]Fax [phone]Email [email protected]: The metabolic enzyme carbonic anhydrase 12 (CA12/CAXII) emerges as a promising cancer therapeutic target with drug development projects underway. Previous reports proposed the relevance of CA12 in the context of glioma but are limited in patient data quantity, ignore ethnic diversity of patients or rely on semi-quantitative, thereby out of date, methodology. Moreover, little is known on the association of CA12 to brain tumor stemness or on the effect of anti-CAXII-directed monotherapies on glioma stem cells (GSCs), in particular their response regarding mesenchymal differentiation status.Methods: We performed in silico analysis on three independent, large-scale patient datasets interrogating state of the art molecular diagnostics alongside clinical outcomes. We analyzed CAXII abundance on a collection of GSCs and functionally tested their response to exposure to CAXII blocking antibody 6A10.Results: CA12 is highly expressed in glial tumors compared with normal tissue and predicts for poor clinical course of tumor patients. CA12 expression in glioblastoma significantly correlates with clinically established, molecular markers of IDH1WT DNA, WHO grade IV or absence of 1p/19q chromosome arm co-deletion. Furthermore, tumors with elevated CA12 cluster into the mesenchymal transcription subclass of the disease. CAXII abundance in different GSCs ranges from almost absent to high levels and does not correlate to stem cell marker CD133/AC133 cell surface expression. Moreover, aiming to pharmacologically block CAXII in our cells with antibody 6A10 caused significant functional response only in one of the tested GSCs models, featuring suppression of cell invasion accompanied by reduction of ZEB1 protein and other stem cell markers.Conclusion: CA12 represents a clinically relevant and molecular brain tumor-subtype specific therapeutic target. Our correlative data from experimental and clinical samples does not support CA12/CAXII to be GSC specific. 6A10 possesses promising potential to impede the invasive capacity of glioma cells and supports the emerging concept that CAXII interacts with cancer EMT programs. However, further mechanistic studies are required to comprehensively assess the therapeutic potential of 6A10 and to identify different resistance mechanisms of GSCs.Keywords: carbonic anhydrase 12, 6A10, glioma, therapeutic antibody, ZEB1, disease modeling

Keywords

• carbonic anhydrase 12
• 6a10
• glioma
• therapeutic antibody
• zeb1
• disease modeling