Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-81299-0
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Funding
- Tour de Cure PhD Support Scholarship [RSP-011-18/19]
- Cancer Institute NSW [2017/AWD002]
- Australian Government Research Training Program Scholarship
- UNSW Sydney Scientia PhD Scholarship (Kokkinos)
- NHMRC [APP1144108]
- Avner Pancreatic Cancer Foundation Innovation Grant [APCF0050618]
- Cancer-Institute NSW ECF/CDFs (Sharbeen) [CDF181166]
- Olivia Lambert Foundation (McCarroll)
- Cancer Australia [APP1126736]
- UNSW Medicine Cancer Theme and SPHERE Cancer Clinical Academic Group E/MCR Seed Grant (Kopecky)
- UNSW International Postgraduate Award (Ritchie)
- Sydney Catalyst Seed Funding Grant (Pereira)
- Lens Ainsworth Fellowship in Pancreatic Cancer Research (Timpson)
- NHMRC Senior Research Fellowship (Timpson) [APP1136974]
- Avner Pancreatic Cancer Foundation Grant (Timpson)
- Beat Cancer Project Principal Cancer Research Fellowship (Butler) [PRF1117]
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This study developed a novel ex vivo explant model that maintains the 3D architecture and microenvironmental cues of human pancreatic ductal adenocarcinoma (PDAC). The model showed advantages over standard organoids, retaining functional multi-cellular stroma and fibrosis, providing unprecedented opportunities for studying PDAC biology and personalized treatment.
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.
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