Serotonin-selective reuptake inhibitors (SSRI) as a novel approach to counteract pancreatic ductal adenocarcinoma progression

Abstract

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is classified as one of the most recalcitrant amongst human malignancies due to its remarkable drug resistance. Nevertheless, little is known regarding the critical processes orchestrating PDAC progression, i.e. pancreatic intraepithelial neoplasia, accumulation of a dense stroma, angiogenesis and inflammatory environment.Aims: We previously demonstrated the role of serotonin (5-HT) in pancreatic inflammation and fibrotic processes during pancreatitis. We now aim to investigate the role of 5-HT in cancer progression and to propose potential new pharmacological strategies to counteract PDAC progression.Materials & methods: Transgenic mice harboring KrasG12D mutation, highly invasive human pancreatic cancer cell line (Panc1), human fibroblasts (HFF) and chick chorioallantoic membrane assay (CAM) were utilized to test the therapeutic potential of serotonin-selective reuptake inhibitors (SSRI). Transcriptome sequencing and imaging assays were used to characterize the effect of SSRI on Panc1 and HFF cell line.Results: Prolonged pharmacological treatment of KrasG12D mice with SSRI significantly reduced pre-malignant acinar cell transformation, along with a blunted desmoplastic stroma and inflammatory cell infiltration. Transcriptome analysis of Panc1 cells revealed that SSRI strongly interfered with cell cycle progression and microtubule assembly, concomitant with increased autophagy. Similar features were observed in SSRI-treated HFF cells displaying concomitant impaired cell motility. Finally, SSRI significantly reduced vessel number and diameter of highly vascularized CAM surfaces.Conclusion: Our data suggest that FDA-approved SSRI display alternative and unexpected clinical implications targeting both pre-malignant lesions and tumor micro-environment. Therefore, SSRI, in combination with chemotherapeutics, may constitute a novel approach to counteract PDAC progression.