@article{60cdcc818f084d388b9f27cfc2a50bb8,
title = "A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids",
abstract = "Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin–integrin α 3/α 6 signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness—a hallmark of pancreatic cancer—was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro. ",
author = "Christopher Below and Joanna Kelly and Alexander Brown and Jonathan Humphries and Colin Hutton and Jingshu Xu and Brian Lee and Celia Cintas and Xiaohong Zhang and Victor Hernandez-Gordillo and Linda Stockdale and Matthew Goldsworthy and Joe Geraghty and Lucy Foster and Derek O'Reilly and Barbara Schedding and Janet Askari and Jessica Burns and Nigel Hodson and Duncan Smith and Catherine Lally and Garry Ashton and David Knight and Aleksandr Mironov and Antonia Banyard and Eble, {Johannes A.} and Morton, {Jennifer P} and Humphries, {Martin James} and Griffith, {Linda G} and Claus Jorgensen",
note = "Funding Information: This work was supported by Cancer Research UK Program grant no. C13329/A21671 (M.J.H., C.J.), Cancer Research UK Institute Awards A19258 (C.J.) and A17196 (J.P.M.), Experimental Medicine Programme Award A25236 (C.J. and J.P.M.), Rosetrees Trust grant no. M286 (C.J.), European Research Council Consolidator Award ERC-2017-COG 772577 (C.J.), National Science Foundation grant no. CBET-0939511 (L.G.G.), National Institutes of Health grants no. R01EB021908 and T32GM008334 (L.G.G.) and Defense Advanced Research Projects Agency grant no. W911NF-12-2-0039 (L.G.G.). J.A.E. is financially supported by the Deutsche Forschungsgemeinschaft (DFG grant no. SFB1009 project A09). We thank D. Liu, A. Thrasher, T. Roberts, B. Torok-Storb, I. Verma, D. Trono and T. Somervaille for kindly sharing plasmids, M.-S. Tsao (UHN) for HPDE H6c7 cells, M. Ball and E. Mckenzie at Manchester Institute of Biotechnology for sortase expression and purification, C. J. Tape at University College London for technical advice, K. Beattie for assistance at FingerPrints Proteomics Facility (University of Dundee), the Cancer Research UK Glasgow Centre (A25142), the Biological Service Unit facilities at CRUK BI and members of Systems Oncology Group at CRUK MI for constructive input. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = jan,
day = "1",
doi = "10.1038/s41563-021-01085-1",
language = "English",
volume = "21",
pages = "110--119",
journal = "Nature Materials",
issn = "1476-1122",
publisher = "Springer Nature",
number = "1",
}
