Patient-derived pancreatic tumours in a dish: implications for real-time precision medicine

Abstract

Introduction: The poor prognosis of pancreatic cancer (PC) is attributed to the highly fibrotic stroma and complex microenvironment that is difficult to fully recapitulate in preclinical models. Mouse models are often derived using human tumour cells without stromal and immune cells, can take months to establish and are confounded by mouse host with human tumour. To fast-track translation of new drugs and to inform PC personalised medicine, there is an unmet need for preclinical models that closely mimic the biology of human disease. Aim: To develop a model that maintains viable human PC tissue in culture for testing therapeutics. Methods: Patient-derived PC tumour tissue was obtained from patients undergoing pancreaticoduodenectomy, cut into 2mm explants, and grown using specialised media on a support scaffold for 12-days ±Abraxane®. Immunohistochemistry was performed for markers of viability, cancer/stromal cell populations and fibrosis. Results: Explants maintained histological tumour and stromal architecture for 12-days of culture. Immunohistochemistry confirmed viable and proliferating cancer and stromal cells that were dispersed throughout dense fibrosis, consistent with day 0 (Figure 1). As proof-of-principle, patient-x explants responded to a clinical dose of Abraxane® with increased cell death. Conclusion: Our novel model retains the 3D architecture of human pancreatic tumours. Our technique has several advantages over standard organoids: 1) no manipulation or digestion of tissue, 2) no artificial propagation of organoids, and 3) presence of functional multi-cellular stroma, fibrosis and vascularity. This provides an unprecedented opportunity to study PC biology, rapidly assess therapeutic response, and could drive personalised treatment for PC.