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Nat Commun ; 12(1): 3834, 2021 06 22.
Article in English | MEDLINE | ID: mdl-34158478

ABSTRACT

H-1 parvovirus (H-1PV) is a promising anticancer therapy. However, in-depth understanding of its life cycle, including the host cell factors needed for infectivity and oncolysis, is lacking. This understanding may guide the rational design of combination strategies, aid development of more effective viruses, and help identify biomarkers of susceptibility to H-1PV treatment. To identify the host cell factors involved, we carry out siRNA library screening using a druggable genome library. We identify one crucial modulator of H-1PV infection: laminin γ1 (LAMC1). Using loss- and gain-of-function studies, competition experiments, and ELISA, we validate LAMC1 and laminin family members as being essential to H-1PV cell attachment and entry. H-1PV binding to laminins is dependent on their sialic acid moieties and is inhibited by heparin. We show that laminins are differentially expressed in various tumour entities, including glioblastoma. We confirm the expression pattern of laminin γ1 in glioblastoma biopsies by immunohistochemistry. We also provide evidence of a direct correlation between LAMC1 expression levels and H-1PV oncolytic activity in 59 cancer cell lines and in 3D organotypic spheroid cultures with different sensitivities to H-1PV infection. These results support the idea that tumours with elevated levels of γ1 containing laminins are more susceptible to H-1PV-based therapies.


Subject(s)
H-1 parvovirus/metabolism , Laminin/metabolism , N-Acetylneuraminic Acid/metabolism , Oncolytic Viruses/metabolism , Virus Attachment , Virus Internalization , Animals , Cell Line, Tumor , Glioblastoma/pathology , Glioblastoma/therapy , Glioblastoma/virology , HCT116 Cells , HEK293 Cells , HeLa Cells , Humans , Laminin/genetics , Mice, Inbred NOD , Mice, SCID , Oncolytic Virotherapy/methods , Protein Binding , RNA Interference , Xenograft Model Antitumor Assays/methods
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