The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target

International Journal of Molecular Sciences

Christoffer F. Nielsen¹  Rikke Raagaard Sørensen²  Henrik Gårdsvoll³  Lars H. Engelholm³  Henrik Jessen Jürgensen³  Eric Santoni-Rugiu³  Oliver Krigslund³  Niels Behrendt³  Pınar Çakılkaya³ 

[1] Adcendo ApS, c/o Copenhagen Bio Science Park (COBIS), 2100 Copenhagen, Denmark;Department of Pathology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark;Finsen Laboratory, Rigshospitalet/Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark;

关键词: uPARAP;    Endo180;    CD280;    MRC2;    mesothelioma;    antibody-drug conjugate;   

DOI  :  10.3390/ijms222111452

来源: DOAJ

【 摘 要 】

Malignant mesothelioma (MM) is a highly aggressive cancer with limited therapeutic options. We have previously shown that the endocytic collagen receptor, uPARAP, is upregulated in certain cancers and can be therapeutically targeted. Public RNA expression data display uPARAP overexpression in MM. Thus, to evaluate its potential use in diagnostics and therapy, we quantified uPARAP expression by immunohistochemical H-score in formalin-fixed paraffin-embedded bioptic/surgical human tissue samples and tissue microarrays. We detected pronounced upregulation of uPARAP in the three main MM subtypes compared to non-malignant reactive mesothelial proliferations, with higher expression in sarcomatoid and biphasic than in epithelioid MM. The upregulation appeared to be independent of patients’ asbestos exposure and unaffected after chemotherapy. Using immunoblotting, we demonstrated high expression of uPARAP in MM cell lines and no expression in a non-malignant mesothelial cell line. Moreover, we showed the specific internalization of an anti-uPARAP monoclonal antibody by the MM cell lines using flow cytometry-based assays and confocal microscopy. Finally, we demonstrated the sensitivity of these cells towards sub-nanomolar concentrations of an antibody-drug conjugate formed with the uPARAP-directed antibody and a potent cytotoxin that led to efficient, uPARAP-specific eradication of the MM cells. Further studies on patient cohorts and functional preclinical models will fully reveal whether uPARAP could be exploited in diagnostics and therapeutic targeting of MM.

【 授权许可】

Unknown