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Published on: November 24, 2014
Oncolytic H-1 parvovirus binds to sialic acid on laminins for cell attachment and entry
Amit Kulkarni1,2, Tiago Ferreira1, Clemens Bretscher1
1Laboratory of Oncolytic Virus Immuno-Therapeutics, German Cancer Research Center, Heidelberg, Germany.
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.
Insights
H-1 parvovirus (H-1PV) shows anticancer promise. Researchers identified laminin gamma 1 (LAMC1) as crucial for H-1PV infection, suggesting LAMC1 levels may predict treatment effectiveness.
Area of Science:
- Virology
- Oncology
- Molecular Biology
Background:
- H-1 parvovirus (H-1PV) is a potential anticancer therapy.
- Understanding H-1PV's host cell interactions is vital for optimizing its use and developing new therapies.
- Identifying host factors can reveal biomarkers for H-1PV treatment susceptibility.
Purpose of the Study:
- To identify host cell factors essential for H-1PV infectivity and oncolysis.
- To explore the role of laminins in H-1PV cell attachment and entry.
- To investigate the correlation between laminin expression and H-1PV efficacy.
Main Methods:
- siRNA library screening of a druggable genome library.
- Loss- and gain-of-function studies, competition assays, and ELISA to validate findings.
- Immunohistochemistry and analysis of cancer cell lines and spheroid cultures to assess laminin expression and H-1PV activity.
Main Results:
- Laminin gamma 1 (LAMC1) was identified as a key modulator of H-1PV infection.
- LAMC1 and other laminins are essential for H-1PV cell attachment and entry, with binding dependent on sialic acid moieties.
- Laminin expression, particularly LAMC1, correlates directly with H-1PV oncolytic activity in various cancer models.
Conclusions:
- Laminin gamma 1 is a critical host factor for H-1PV infection.
- Tumors with high levels of gamma 1-containing laminins may be more susceptible to H-1PV therapy.
- These findings provide a basis for developing targeted H-1PV treatment strategies and identifying patient biomarkers.
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