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

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. Th...

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Autores principales:	Pınar Çakılkaya, Rikke Raagaard Sørensen, Henrik Jessen Jürgensen, Oliver Krigslund, Henrik Gårdsvoll, Christoffer F. Nielsen, Eric Santoni-Rugiu, Niels Behrendt, Lars H. Engelholm
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	uPARAP Endo180 CD280 MRC2 mesothelioma antibody-drug conjugate Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/bf9c3787659c42d8b0502307136ed2ba
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spelling	oai:doaj.org-article:bf9c3787659c42d8b0502307136ed2ba2021-11-11T16:54:51ZThe Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target10.3390/ijms2221114521422-00671661-6596https://doaj.org/article/bf9c3787659c42d8b0502307136ed2ba2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11452https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Malignant 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.Pınar ÇakılkayaRikke Raagaard SørensenHenrik Jessen JürgensenOliver KrigslundHenrik GårdsvollChristoffer F. NielsenEric Santoni-RugiuNiels BehrendtLars H. EngelholmMDPI AGarticleuPARAPEndo180CD280MRC2mesotheliomaantibody-drug conjugateBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11452, p 11452 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	uPARAP Endo180 CD280 MRC2 mesothelioma antibody-drug conjugate Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	uPARAP Endo180 CD280 MRC2 mesothelioma antibody-drug conjugate Biology (General) QH301-705.5 Chemistry QD1-999 Pınar Çakılkaya Rikke Raagaard Sørensen Henrik Jessen Jürgensen Oliver Krigslund Henrik Gårdsvoll Christoffer F. Nielsen Eric Santoni-Rugiu Niels Behrendt Lars H. Engelholm The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target
description	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.
format	article
author	Pınar Çakılkaya Rikke Raagaard Sørensen Henrik Jessen Jürgensen Oliver Krigslund Henrik Gårdsvoll Christoffer F. Nielsen Eric Santoni-Rugiu Niels Behrendt Lars H. Engelholm
author_facet	Pınar Çakılkaya Rikke Raagaard Sørensen Henrik Jessen Jürgensen Oliver Krigslund Henrik Gårdsvoll Christoffer F. Nielsen Eric Santoni-Rugiu Niels Behrendt Lars H. Engelholm
author_sort	Pınar Çakılkaya
title	The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target
title_short	The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target
title_full	The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target
title_fullStr	The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target
title_full_unstemmed	The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target
title_sort	collagen receptor uparap in malignant mesothelioma: a potential diagnostic marker and therapeutic target
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/bf9c3787659c42d8b0502307136ed2ba
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The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target

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