TY - JOUR

T1 - The Collagen Receptor uPARAP in Malignant Mesothelioma

T2 - A Potential Diagnostic Marker and Therapeutic Target

AU - Çakılkaya, Pınar

AU - Sørensen, Rikke Raagaard

AU - Jürgensen, Henrik Jessen

AU - Krigslund, Oliver

AU - Gårdsvoll, Henrik

AU - Nielsen, Christoffer F.

AU - Santoni‐Rugiu, Eric

AU - Behrendt, Niels

AU - Engelholm, Lars H.

N1 - Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - ADC

KW - Antibody‐drug conjugate

KW - CD280

KW - Endo180

KW - Extracellular matrix

KW - Immunohistochemistry

KW - Mesothelioma

KW - MRC2

KW - Tumor microenvironment

KW - UPARAP

U2 - 10.3390/ijms222111452

DO - 10.3390/ijms222111452

M3 - Journal article

C2 - 34768883

AN - SCOPUS:85117490372

VL - 22

JO - International Journal of Molecular Sciences (CD-ROM)

JF - International Journal of Molecular Sciences (CD-ROM)

SN - 1424-6783

IS - 21

M1 - 11452

ER -