Inhibition of the Complement Pathway Induces Cellular Proliferation and Migration in Pancreatic Ductal Adenocarcinoma

Abstract

AbstractPancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a growing incidence and mortality despite novel therapeutic strategies. The complement signalling pathway may play diverse roles in PDAC by eliciting an immune response, inducing inflammatory responses, and may elevate pathways linked to chemoresistance. However, their role in the progression of PDAC is not fully understood. In this study, 30 tissues and 34 plasma samples were obtained from a cohort of PDAC patients including controls. Targeted pathway-specific PCR analysis was conducted to determine the gene expression profiles of immune-response-related genes. The circulating levels of complement proteins C3 and C5 were further investigated. Pharmacological inhibition of the complement pathway in MIA PaCa-2 pancreatic cancer cell lines was performed and the effect on cells was assessed by cell proliferation, cell migration, and cell cycle assays. Finally, SWATH-mass spectrometry was performed to identify potential molecular mechanisms during inhibition. The results identified C3 and C5 to be overly expressed in early PDAC compared to later stages. Pharmacological inhibition of the complement pathway led to increased cell growth, proliferation and migrationin vitro. Proteomic analysis implicated several proteins such as the mitochondrial and histone proteins, that could play a role in inducing this phenotype. This study helps to further delineate the role of the complement pathway in PDAC progression suggesting a context-dependent function.