Abstract
The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attributed to the highly fibrotic stroma and complex multi-cellular microenvironment that is difficult to fully recapitulate in pre-clinical models. To fast-track translation of therapies and to inform personalised medicine, we aimed to develop a whole-tissue ex vivo explant model that maintains viability, 3D multicellular architecture, and microenvironmental cues of human pancreatic tumours. Patient-derived surgically-resected PDAC tissue was cut into 1–2 mm explants and cultured on gelatin sponges for 12 days. Immunohistochemistry revealed that human PDAC explants were viable for 12 days and maintained their original tumour, stromal and extracellular matrix architecture. As proof-of-principle, human PDAC explants were treated with Abraxane and we observed different levels of response between patients. PDAC explants were also transfected with polymeric nanoparticles + Cy5-siRNA and we observed abundant cytoplasmic distribution of Cy5-siRNA throughout the PDAC explants. Overall, our novel model retains the 3D architecture of human PDAC and has advantages over standard organoids: presence of functional multi-cellular stroma and fibrosis, and no tissue manipulation, digestion, or artificial propagation of organoids. This provides unprecedented opportunity to study PDAC biology including tumour-stromal interactions and rapidly assess therapeutic response to drive personalised treatment.
Highlights
Identify existing drugs that will be effective on a patient’s individual tumour, there is an unmet need to develop better pre-clinical models that are: (1) easy to establish; (2) cost-effective; (3) provide results in a timely manner to inform patient treatment; (4) avoid mechanical or enzymatic digestion of tissue; and (5) closely reflect the biology of human disease
We describe the development and characterisation of a novel human pre-clinical model of pancreatic ductal adenocarcinoma (PDAC) that maintains the viability, 3D multicellular architecture and microenvironmental cues of unmanipulated patient derived tumours
For the efficacy of new therapeutic strategies to be evaluated, there is a need for robust pre-clinical models that accurately reflect the biology of the disease in patients
Summary
Identify existing drugs that will be effective on a patient’s individual tumour, there is an unmet need to develop better pre-clinical models that are: (1) easy to establish; (2) cost-effective; (3) provide results in a timely manner to inform patient treatment; (4) avoid mechanical or enzymatic digestion of tissue; and (5) closely reflect the biology of human disease. Organoids often lack a fibrotic stroma and the presence of CAFs and blood vessels Taken together, these limitations highlight the need to develop more clinically relevant models of PDAC to complement the other models available. We have developed a new PDAC pre-clinical model that retains the 3D architecture of human patient derived PDAC tumours This model does not involve any chemical, enzymatic, or mechanical digestion of PDAC tissue and avoids artificially skewing cell populations. We further demonstrate that this model can be applied to test both clinically approved chemotherapy drugs as well as novel therapeutics including a nano-based gene silencing drug developed in our lab This new model provides a unique opportunity to closely study the biology of the PDAC tumour microenvironment, to identify novel gene targets and test new treatment strategies in a cost-effective and timely manner
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