Gastrointestinal cancer-associated fibroblasts expressing Junctional Adhesion Molecule-A are amenable to infection by oncolytic reovirus

Tom J. Harryvan, Matteo Golo, Nicole Dam, Mark J.A. Schoonderwoerd, Elham Aida Farshadi, Marten Hornsveld, Rob C. Hoeben, Lukas J.A.C. Hawinkels, Vera Kemp*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Gastrointestinal (GI) cancers are characterized by extensive tumor stroma that both promotes tumor progression and acts as a physical barrier for adjacent tumor cells, limiting the effect of current treatment modalities. Oncolytic virotherapy is currently investigated in clinical trials as a novel therapeutic agent for different malignancies of the GI tract, but it is largely unknown whether these viruses can also target the tumor stroma. Here, we investigated the tropism of two commonly studied OVs, adenovirus and reovirus, towards primary GI fibroblasts from human oesophageal, gastric, duodenal and pancreatic carcinomas (N = 36). GI fibroblasts were susceptible to type 3 Dearing (T3D) strain R124 and bioselected mutant reovirus (jin-3) infection but not oncolytic adenovirus (Ad5-Δ24). Efficient infection and apoptosis of human and mouse GI cancer-derived fibroblasts by these reoviruses was partially dependent on the expression of the reovirus entry receptor, Junctional Adhesion Molecule-A (JAM-A). Moreover, human GI cancer organoid-fibroblast co-cultures showed higher overall infectivity when containing JAM-A expressing fibroblasts as compared to JAM-A negative fibroblasts, indicating a potential role of JAM-A expressing fibroblasts for viral dissemination. We further show that JAM-A is not only necessary for efficient reovirus infection of fibroblasts but also partially mediates reovirus-induced apoptosis, dependent on signaling through the C-terminal PDZ-domain of JAM-A. Altogether, our data show the presence of JAM-A expressing fibroblasts in both human and murine GI cancers that are amenable to infection and induction of apoptosis by reovirus, extending the potential anti-cancer actions of reovirus with stromal targeting.

Original languageEnglish
Pages (from-to)1918-1929
Number of pages12
JournalCancer Gene Therapy
Volume29
Issue number12
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
TJH is sponsored by a personal MD-PhD grant from the Leiden University Medical Center. VK is supported by a personal grant from the Dutch Research Council (NWO-talent program Veni, ZonMw). VK and EAF received funding from the Foundation “Overleven met Alvleesklierkanker”, Utrecht, Netherlands (SOAK 21.02) for the employment of ND.

Publisher Copyright: © 2022, The Author(s).

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