Ex vivo culture of intact human patient derived pancreatic tumour tissue

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, w...

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Autores principales:	John Kokkinos, George Sharbeen, Koroush S. Haghighi, Rosa Mistica C. Ignacio, Chantal Kopecky, Estrella Gonzales-Aloy, Janet Youkhana, Paul Timpson, Brooke A. Pereira, Shona Ritchie, Elvis Pandzic, Cyrille Boyer, Thomas P. Davis, Lisa M. Butler, David Goldstein, Joshua A. McCarroll, Phoebe A. Phillips
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c376c5a5ce784e57bf7955dbb27bd3ff
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spelling	oai:doaj.org-article:c376c5a5ce784e57bf7955dbb27bd3ff2021-12-02T10:49:16ZEx vivo culture of intact human patient derived pancreatic tumour tissue10.1038/s41598-021-81299-02045-2322https://doaj.org/article/c376c5a5ce784e57bf7955dbb27bd3ff2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81299-0https://doaj.org/toc/2045-2322Abstract 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.John KokkinosGeorge SharbeenKoroush S. HaghighiRosa Mistica C. IgnacioChantal KopeckyEstrella Gonzales-AloyJanet YoukhanaPaul TimpsonBrooke A. PereiraShona RitchieElvis PandzicCyrille BoyerThomas P. DavisLisa M. ButlerDavid GoldsteinJoshua A. McCarrollPhoebe A. PhillipsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q John Kokkinos George Sharbeen Koroush S. Haghighi Rosa Mistica C. Ignacio Chantal Kopecky Estrella Gonzales-Aloy Janet Youkhana Paul Timpson Brooke A. Pereira Shona Ritchie Elvis Pandzic Cyrille Boyer Thomas P. Davis Lisa M. Butler David Goldstein Joshua A. McCarroll Phoebe A. Phillips Ex vivo culture of intact human patient derived pancreatic tumour tissue
description	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.
format	article
author	John Kokkinos George Sharbeen Koroush S. Haghighi Rosa Mistica C. Ignacio Chantal Kopecky Estrella Gonzales-Aloy Janet Youkhana Paul Timpson Brooke A. Pereira Shona Ritchie Elvis Pandzic Cyrille Boyer Thomas P. Davis Lisa M. Butler David Goldstein Joshua A. McCarroll Phoebe A. Phillips
author_facet	John Kokkinos George Sharbeen Koroush S. Haghighi Rosa Mistica C. Ignacio Chantal Kopecky Estrella Gonzales-Aloy Janet Youkhana Paul Timpson Brooke A. Pereira Shona Ritchie Elvis Pandzic Cyrille Boyer Thomas P. Davis Lisa M. Butler David Goldstein Joshua A. McCarroll Phoebe A. Phillips
author_sort	John Kokkinos
title	Ex vivo culture of intact human patient derived pancreatic tumour tissue
title_short	Ex vivo culture of intact human patient derived pancreatic tumour tissue
title_full	Ex vivo culture of intact human patient derived pancreatic tumour tissue
title_fullStr	Ex vivo culture of intact human patient derived pancreatic tumour tissue
title_full_unstemmed	Ex vivo culture of intact human patient derived pancreatic tumour tissue
title_sort	ex vivo culture of intact human patient derived pancreatic tumour tissue
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c376c5a5ce784e57bf7955dbb27bd3ff
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Ex vivo culture of intact human patient derived pancreatic tumour tissue

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