Identifying genetic expression patterns as marker for sensitivity to oncolytic viruses using patient-derived pancreatic ductal adenocarcinoma organoids
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a poor prognosis. Viro-immunotherapy using oncolytic viruses (OVs) represents a promising treatment for PDAC. However, PDACs from different patients respond differently to OV therapies, highlighting the need for predictive biomarkers to optimize outcomes. This study aimed to identify gene expression profiles (GEPs) that could serve as predictors for OV sensitivity. Experimental design: Patient-derived organoids (PDOs) from ten PDAC patients were assessed for sensitivity to various OVs: Newcastle Disease Virus, a Reovirus strain entering cells independently of JAM-A expression, the Edmonston vaccine strain of Measles Virus, and a gorilla-derived adenovirus. To identify GEPs with predictive value, OV sensitivity was correlated with the transcriptome of uninfected PDOs. These GEPs were analyzed in the Gene Ontology database to reveal biological processes associated with them. Results: PDOs showed heterogenic responses to OVs, with nine of ten being sensitive to at least one. Analysis of the generated GEPs using the Gene Ontology database identified intracellular aberrations as the primary determinant of OV sensitivity. Sensitivity to all OVs was associated with GEPs related to embryonic development, while varied sensitivity of the ten PDOs to four OVs was linked to cell cycle regulation, metabolism, and proliferation. Conclusions: This study revealed that OV sensitivity was associated with GEPs comprising genes involved in multiple biological processes. Further investigation into screening tumors for the identified GEPs may yield biomarkers for selecting the most effective OV for PDAC. This approach is a stepping stone toward personalized OV treatments. Overall design: RNA-seq profiling of ten uninfected PDAC PDOs