Abstract
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.
Highlights
MM is a highly aggressive cancer type originating from the mesothelium lining the pleura or other serosal cavities, including the peritoneum, pericardium, and tunica vaginalis testis
Since uPARAP was found to be strongly upregulated in MM, we investigated by western blot (WB) analysis whether the expression would be retained in human MM‐ derived cell lines and whether these cells could be used as tools to study uPARAP‐ directed tumor targeting in vitro
This study provides a detailed elucidation of the expression of uPARAP, a potential diagnostic marker and therapeutic target, in MM
Summary
MM is a highly aggressive cancer type originating from the mesothelium lining the pleura or other serosal cavities, including the peritoneum, pericardium, and tunica vaginalis testis. MM is a challenging disease due to its heterogeneity, often delayed diagnosis with conventional methods and inadequate response to current treatment options. EMM is associated with a somewhat better prognosis than the two other subtypes, while SMM has the poorest outcome in patients [1]. The treatment options for unresectable MM (75% of all cases) are very limited, given the poor efficacy of the current approved standard chemotherapy with the platin‐ pemetrexed doublet. These insufficient options and the hitherto disappointing attempts with targeted therapies against MM signaling pathways lately urged potential immunotherapy‐based strategies to be developed against this malignancy [3,4,5]. There remains a crucial unmet need for identifying novel and effective therapeutic targets for MM
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