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BMC Cancer. 2017 Aug 30;17(1):594. doi: 10.1186/s12885-017-3600-2.

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

Author information

1
Translational Ovarian Cancer Research Program, London, ON, Canada.
2
Department of Anatomy & Cell Biology, Western University, London, ON, Canada.
3
Translational Head and Neck Cancer Research Program, London, ON, Canada.
4
Department of Medicine & Biochemistry, University of Ottawa, Ottawa, ON, Canada.
5
Department of Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
6
Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
7
Department of Biochemistry, Western University, London, ON, Canada.
8
Department of Oncology, Western University, London, ON, Canada.
9
Translational Ovarian Cancer Research Program, London, ON, Canada. tshephe6@uwo.ca.
10
Department of Anatomy & Cell Biology, Western University, London, ON, Canada. tshephe6@uwo.ca.
11
Department of Oncology, Western University, London, ON, Canada. tshephe6@uwo.ca.
12
Department of Obstetrics & Gynaecology, Western University, London, ON, Canada. tshephe6@uwo.ca.
13
London Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, ON, N6A 4L6, Canada. tshephe6@uwo.ca.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Ascites; High-grade serous ovarian cancer; Maraba virus; Oncolytic virus; Resistance; Tumour heterogeneity

PMID:
28854921
PMCID:
PMC5577660
DOI:
10.1186/s12885-017-3600-2
[Indexed for MEDLINE]
Free PMC Article

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