Virus-Tumor Interactome Screen Reveals ER Stress Response Can Reprogram Resistant Cancers for Oncolytic Virus-Triggered Caspase-2 Cell Death

Abstract

To identify therapeutic opportunities for oncolytic viral therapy, we conducted genome-wide RNAi screens to search for host factors that modulate rhabdoviral oncolysis. Our screens uncovered the endoplasmic reticulum (ER) stress response pathways as important modulators of rhabdovirus-mediated cytotoxicity. Further investigation revealed an unconventional mechanism whereby ER stress response inhibition preconditioned cancer cells, which sensitized them to caspase-2-dependent apoptosis induced by a subsequent rhabdovirus infection. Importantly, this mechanism was tumor cell specific, selectively increasing potency of the oncolytic virus by up to 10,000-fold. In vivo studies using a small molecule inhibitor of IRE1α showed dramatically improved oncolytic efficacy in resistant tumor models. Our study demonstrates proof of concept for using functional genomics to improve biotherapeutic agents for cancer.

Danger signalling during cancer cell death: origins, plasticity and regulation

“…6,17 The reliance on the joint induction of ROS and ER stress for the efficient emission of DAMPs is perhaps not surprising Abbreviations: ATP, adenosine triphosphate; CRT, calreticulin; DAMP, damage-associated molecular patterns; GRP, glucose-regulated protein; HMGB1, high mobility group box-1; HSP, heat shock protein; ICD, immunogenic cell death; PDT, photodynamic therapy; UVC, ultraviolet C a Oncolytic viruses can cause necrosis in cancer cells 119 as well as apoptosis. 120 Specifically, in the aforementioned study, the authors confirmed that CVB3-induced ICD was of apoptotic nature through analysis of phosphatidylserine externalization (in the absence/presence of permeabilization) and DNA fragmentation. 26 b It has to be considered that cyclophosphamide's effects on anti-tumour immunity are strongly dose-dependent.…”

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

“…The IRE1α/XBP1 pathway is often activated in cancers and has recently emerged as a potential molecular target for anticancer therapy (1,5,(39)(40)(41)(42)(43), especially for multiple myeloma, which is characterized by malignant plasma cells producing a high amount of immunoglobulin (26,42,44,45). These previous studies showed that the pharmacological inhibition of IRE1α endonuclease significantly suppressed myeloma tumor growth in a model of human malignant myeloma xenografts, corroborating the idea that the IRE1α/XBP1 pathway may serve as a promising molecular target.…”

Caspase-2 at a glance

“…Both viruses are known to induce a strong ER or unfolded protein stress response (UPR), which can lead to apoptosis (Mahoney et al, 2011). Interestingly, by keeping protein levels of RAIDD low, the ERstress response machinery appears to be able to delay caspase-2-dependent apoptosis upon infection (Mahoney et al, 2011).…”

“…Both viruses are known to induce a strong ER or unfolded protein stress response (UPR), which can lead to apoptosis (Mahoney et al, 2011). Interestingly, by keeping protein levels of RAIDD low, the ERstress response machinery appears to be able to delay caspase-2-dependent apoptosis upon infection (Mahoney et al, 2011). Under conditions of sustained ER stress, however, the ER stress response factor IRE1a (also known as ERN1), an ER transmembrane kinase-endoribonuclease (RNase), promotes the rapid degradation of microRNAs that target caspase-2 mRNA.…”