Spatial and temporal epithelial ovarian cancer cell heterogeneity impacts Maraba virus oncolytic potential

• Published in: BMC cancer Vol. 17; no. 1; p. 594
• Main Authors: Tong, Jessica G, Valdes, Yudith Ramos, Sivapragasam, Milani, Barrett, John W, Bell, John C, Stojdl, David, DiMattia, Gabriel E, Shepherd, Trevor G
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.08.2017; BioMed Central; BMC
• Subjects: Ascites; Cancer cells; Cancer therapies; Carcinoma, Ovarian Epithelial; Care and treatment; Causes of; Cell adhesion; Cell culture; Cell Line, Tumor; Chemotherapy; Coculture Techniques - methods; Development and progression; Differential media; Genetic aspects; Genetic Heterogeneity; High-grade serous ovarian cancer; Humans; Interferon; Low density lipoprotein receptors; Maraba virus; Medical prognosis; Metastasis; Neoplasms, Glandular and Epithelial - pathology; Neoplasms, Glandular and Epithelial - virology; Oncogenic viruses; Oncolysis; Oncolytic Virotherapy - methods; Oncolytic virus; Oncolytic Viruses - physiology; Ovarian cancer; Ovarian Neoplasms - pathology; Ovarian Neoplasms - virology; Physiological aspects; Receptor density; Resistance; Tumor cell lines; Tumors; Tumour heterogeneity; Viruses; Canada; Resistance; Tumour heterogeneity; Oncolytic virus; Ascites; Maraba virus; High-grade serous ovarian cancer
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-017-3600-2

Epithelial ovarian cancer exhibits extensive interpatient and intratumoral heterogeneity, which can hinder successful treatment strategies. Herein, we investigated the efficacy of an emerging oncolytic, Maraba virus (MRBV), in an in vitro model of ovarian tumour heterogeneity. Four ovarian high-grade serous cancer (HGSC) cell lines were isolated and established from a single patient at four points during disease progression. Limiting-dilution subcloning generated seven additional subclone lines to assess intratumoral heterogeneity. MRBV entry and oncolytic efficacy were assessed among all 11 cell lines. Low-density receptor (LDLR) expression, conditioned media treatments and co-cultures were performed to determine factors impacting MRBV oncolysis. Temporal and intratumoral heterogeneity identified two subpopulations of cells: one that was highly sensitive to MRBV, and another set which exhibited 1000-fold reduced susceptibility to MRBV-mediated oncolysis. We explored both intracellular and extracellular mechanisms influencing sensitivity to MRBV and identified that LDLR can partially mediate MRBV infection. LDLR expression, however, was not the singular determinant of sensitivity to MRBV among the HGSC cell lines and subclones. We verified that there were no apparent extracellular factors, such as type I interferon responses, contributing to MRBV resistance. However, direct cell-cell contact by co-culture of MRBV-resistant subclones with sensitive cells restored virus infection and oncolytic killing of mixed population. Our data is the first to demonstrate differential efficacy of an oncolytic virus in the context of both spatial and temporal heterogeneity of HGSC cells and to evaluate whether it will constitute a barrier to effective viral oncolytic therapy.