Oncolytic H-1 parvovirus binds to sialic acid on laminins for cell attachment and entry

Amit Kulkarni, Tiago Ferreira, Clemens Bretscher, Annabel Grewenig, Nazim El-Andaloussi, Serena Bonifati, Tiina Marttila, Valérie Palissot, Jubayer A. Hossain, Francisco Azuaje, Hrvoje Miletic, Lars A. R. Ystaas, Anna Golebiewska, Simone P. Niclou, Ralf Roeth, Beate Niesler, Amélie Weiss, Laurent Brino and Antonio Marchini ()
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Amit Kulkarni: Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center
Tiago Ferreira: Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center
Clemens Bretscher: Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center
Annabel Grewenig: Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center
Nazim El-Andaloussi: Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center
Serena Bonifati: Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center
Tiina Marttila: Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center
Valérie Palissot: Laboratory of Oncolytic Virus Immuno-Therapeutics, Luxembourg Institute of Health
Jubayer A. Hossain: Laboratory of Oncolytic Virus Immuno-Therapeutics, Luxembourg Institute of Health
Francisco Azuaje: Quantitative Biology Unit, Luxembourg Institute of Health
Hrvoje Miletic: University of Bergen
Lars A. R. Ystaas: University of Bergen
Anna Golebiewska: NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health
Simone P. Niclou: NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health
Ralf Roeth: University of Heidelberg
Beate Niesler: University of Heidelberg
Amélie Weiss: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Laurent Brino: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
Antonio Marchini: Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24034-7

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