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

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a growing incidence and mortality despite novel therapeutic strategies. Its aggressiveness and difficulty in treatment suggest the need for a better understanding of associated molecular mechanisms that could be targeted for treatment. The complement signalling pathway may play diverse roles in PDAC by eliciting an immune response, inducing inflammatory responses, and elevating pathways linked to chemoresistance. However, their role in the progression of PDAC is not fully understood. This study aimed to identify potential immune response-related targets in a group of patients. Methods: Thirty tissue samples (tumours and corresponding normal tissues) were obtained from 15 PDAC patients, 34 plasma samples from 25 PDAC patients, six patients with chronic pancreatitis, and three healthy control participants. Targeted pathway-specific polymerase chain reaction (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 was assessed by cell proliferation, cell migration, and cell cycle assays. Finally, Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) was performed to identify potential molecular mechanisms during inhibition. Results: The results identified C3 as overly expressed in early PDAC compared to later stages in plasma (p = 0.047). Pharmacological inhibition of the complement pathway led to increased cell growth (p < 0.0001), proliferation (p = 0.001) and migration (p = 0.002) in vitro. Proteomic analysis implicated several proteins, such as the mitochondrial and histone proteins, that could play a role in inducing this phenotype. Conclusion: Complement C3 and C5 are elevated in PDAC samples compared to healthy ones. Furthermore, the inhibition of the complement pathway was shown in vitro to result in a more aggressive phenotype by stimulating cellular growth, proliferation, and migration, indicating the involvement of complement C3 and C5 in tumour progression. This study helps to delineate further the role of the complement pathway in PDAC progression.