Oncolytic H-1 Parvovirus Hijacks Galectin-1 to Enter Cancer Cells

Abstract

Clinical studies in glioblastoma and pancreatic carcinoma patients strongly support the further development of H-1 protoparvovirus (H-1PV)-based anticancer therapies. The identification of cellular factors involved in the H-1PV life cycle may provide the knowledge to improve H-1PV anticancer potential. Recently, we showed that sialylated laminins mediate H-1PV attachment at the cell membrane. In this study, we revealed that H-1PV also interacts at the cell surface with galectin-1 and uses this glycoprotein to enter cancer cells. Indeed, knockdown/out of LGALS1, the gene encoding galectin-1, strongly decreases the ability of H-1PV to infect and kill cancer cells. This ability is rescued by the re-introduction of LGALS1 into cancer cells. Pre-treatment with lactose, which is able to bind to galectins and modulate their cellular functions, decreased H-1PV infectivity in a dose dependent manner. In silico analysis reveals that LGALS1 is overexpressed in various tumours including glioblastoma and pancreatic carcinoma. We show by immunohistochemistry analysis of 122 glioblastoma biopsies that galectin-1 protein levels vary between tumours, with levels in recurrent glioblastoma higher than those in primary tumours or normal tissues. We also find a direct correlation between LGALS1 transcript levels and H-1PV oncolytic activity in 53 cancer cell lines from different tumour origins. Strikingly, the addition of purified galectin-1 sensitises poorly susceptible GBM cell lines to H-1PV killing activity by rescuing cell entry. Together, these findings demonstrate that galectin-1 is a crucial determinant of the H-1PV life cycle.

Biomarker screen for efficacy of oncolytic virotherapy in patient-derived pancreatic cancer cultures

“…PV was recently shown to depend on the expression of Laminin C1 (LAMC1) and Galectin-1 (LGALS1) for cell entry. 55 Despite similar expression levels across all cultures, there was a weak correlation of reduction in cell viability with higher expression of Galectin-1, as shown in Fig. 4 b.…”

“…S7 ) identified 44 common genes in the siRNA screen and 27 common genes in the NCI-60 screen associated with sensitivity to PV. Notably, Galectin-1 (LGALS1), which was described to have a role in PV entry, 55 was the single common factor associated with sensitivity across all three screens (compare Fig. 4 b), underlining its importance in the PV replication cycle.…”

Combination of Oncolytic Virotherapy with Different Antitumor Approaches against Glioblastoma

“…H-1PV is a small rat protoparvovirus, a member of the Parvoviridae family with linear single-stranded DNA molecules. The cytotoxicity of recombinant parvovirus is attributed to the viral regulatory nonstructural protein NS1, characterized as the major regulator of viral DNA replication and transcription [59]. The natural host of H-1PV is the rat; in humans, it is nonpathogenic.…”

Oncolytic viral therapy as promising immunotherapy against glioma

“…H‐1 parvovirus (H‐1PV) is a self‐propagating virus with oncolytic and tumor‐suppressing activity and is nonpathogenic in humans 165 . H‐1PV interacts with galactactagglutinin‐1 to enter cancer cells, and the LGALS1 gene (encoding galectin‐1) is overexpressed in glioblastoma cells 166 . In immunocompetent rat models of rat (RG‐2 cell‐derived) and immunodeficiencies rat models of human (U87 cell‐derived) glioma, a single stereotactic intratumor‐injected H‐1PV and multiple systemic (iv) application of H‐1PV significantly improved survival in rat and human glioma models 167 …”