Integrative Proteomic Analysis Reveals VMG Oncolytic Virus-Induced Molecular Reprogramming in Pancreatic Ductal...

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of 13.3%. This study investigates the treatment efficacy of VMG, a chimeric oncolytic vesiculovirus, against PDAC, focusing on its mechanism and therapeutic potential. VMG is engineered to replace the Vesicular Stomatitis Virus (VSV) glycoprotein (G) gene with the Morreton virus (MorV) glycoprotein, enhancing its safety, efficacy, and immune infiltration compared to wild-type VSV. We conducted an in-depth proteomic analysis of VMG treatment and evaluated its in vitro and in vivo efficacy. Our findings indicate that VMG treatment not only induces apoptosis and reduces tumor cell viability in PDAC cell lines, but also significantly slows tumor growth and enhances survival in PDAC mouse models. We then explored whether proteomic analysis could help uncover the mechanistic underpinnings of this efficacy. This approach allowed us to investigate the biological pathways involved in VMG's action. To understand these mechanisms, proteomic data were integrated with information from Ingenuity Pathway Analysis (IPA), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and The Cancer Genome Atlas (TCGA). This analysis aimed to identify the key signaling pathways modulated by VMG. By integrating efficacy testing with proteomic and pathway analyses, we sought to clarify how VMG exerts its molecular effects. This approach offers a strong framework for uncovering the biological processes influenced by VMG. The study reveals that VMG treatment leads to a substantial overlap between virus-induced proteomic changes and prognostic markers found in the TCGA PDAC cohort. Specifically, VMG downregulates proteins associated with unfavorable prognosis, including those involved in altered mitochondrial function, genome DNA synthesis and repair, RNA modification, ribosome biogenesis, intracellular trafficking, cell cycle control, cytoskeletal dynamics, and palmitoylation. This multifaceted oncolytic mechanism disrupts fundamental processes driving PDAC progression, survival, and chemoresistance, providing a robust foundation for identifying novel therapeutic targets and biomarkers.