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A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids

Nature Materials volume 21, pages 110–119 (2022)Cite this article

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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 α3/α6 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.

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Fig. 1: Defining adhesive requirements of PCCs.
Fig. 2: Optimizing PEG hydrogel composition for pancreatic organoids.
Fig. 3: Formation of hPDOs in defined PEG matrices.
Fig. 4: Recapitulating the stiffness range of PDA in PEG hydrogels.
Fig. 5: 3D PEG-VS CBF-0.5 gels support stromal co-cultures.

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Data availability

All original source data are freely available. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE69 partner repository with the following dataset identifiers: NP matrisome atlas (PXD022555 and 10.6019/PXD022555); IAC datasets (PXD022487 and 10.6019/PXD022487); cell-derived matrix datasets (PXD022509 and 10.6019/PXD022509); 3D PEG CBF-0.5 LC–MS (PXD022520 and 10.6019/PXD022520); Tumour Matrisome LC–MS (PXD022767 and 10.6019/PXD022767). Raw CyTOF data, IF images and AFM force curves as well as source data for all figures (Figs. 1–5 and Supplementary Figs. 1–28) have been deposited to https://zenodo.org/record/4664132.

Code availability

All original R scripts have been deposited to https://zenodo.org/record/4664132 and are freely available.

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Acknowledgements

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.

Author information

Author notes

  1. Jonathan D. Humphries

    Present address: Department of Life Science, Manchester Metropolitan University, Manchester, UK

Authors and Affiliations

  1. Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK

    Christopher R. Below, Joanna Kelly, Colin Hutton, Jingshu Xu, Brian Y. Lee, Celia Cintas, Xiaohong Zhang, Duncan L. Smith, Catherine Lally, Garry Ashton, Antonia Banyard & Claus Jørgensen

  2. Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Christopher R. Below, Jonathan D. Humphries, Janet Askari, Jessica Burns & Martin J. Humphries

  3. Centre for Gynepathology Research, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Alexander Brown, Victor Hernandez-Gordillo, Linda Stockdale & Linda G. Griffith

  4. Manchester Royal Infirmary, Manchester, UK

    Matthew A. Goldsworthy, Joe Geraghty, Lucy Foster & Derek A. O’Reilly

  5. Institute for Physiological Chemistry and Pathobiochemistry, University of Muenster, Muenster, Germany

    Barbara Schedding & Johannes A. Eble

  6. BioAFM Laboratory, Bioimaging Core Facility, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Nigel Hodson

  7. Biological Mass Spectrometry Core Facility, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    David Knight

  8. Electron Microscopy Core Facility, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Aleksandr Mironov

  9. Cancer Research UK Beatson Institute, Glasgow, UK

    Jennifer P. Morton

  10. Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

    Jennifer P. Morton

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  1. Christopher R. Below
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Contributions

C.R.B., J.K., A. Brown, B.Y.L., J.D.H., D.L.S., L.G.G., M.J.H. and C.J. designed the research; C.R.B., J.K., A. Brown, A. Banyard, J.D.H., J.X., C.L., D.K., A.M., N.H., D.L.S., J.B., C.C. and B.Y.L. conducted experiments; C.R.B., J.K., A. Brown, A. Banyard and C.J. analysed data; A. Banyard, C.C., V.H.-G., L.S., J.A.E., B.S., X.Z., D.L.S., D.K., J.A., G.A. and C.H. provided technical support; J.P.M. maintained the genetically engineered murine models and provided murine samples; J.P.M., L.S., L.G.G., J.A.E. and B.S. provided reagents and cell lines; M.A.G., J.G., L.F. and D.A.O. helped with clinical sample collection; L.F. provided pathological support; C.R.B. and C.J. wrote the paper and C.J. and L.G.G. oversaw the project. J.X. contributed to this work while an employee at CRUK MI.

Corresponding authors

Correspondence to Linda G. Griffith or Claus Jørgensen.

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Competing interests

L.G.G. has patent application pending related to the hydrogel system. The rest of the authors have no competing interests.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–28, Tables 1 and 2, Methods, legends for Supplementary Videos 1–15, uncropped blots and FACS gating strategy.

Reporting Summary

Supplementary Video 1

Time-lapse image series of KPC-1 PCCs adhering to laminin 511.

Supplementary Video 2

Time-lapse image series of KPC-1 PCCs adhering to a non-coated surface.

Supplementary Video 3

Time-lapse image series of KPC-1 PCCs adhering to laminin 511.

Supplementary Video 4

Time-lapse image series of KPC-1 PCCs adhering to laminin 521.

Supplementary Video 5

Time-lapse image series of KPC-1 PCCs adhering to a combination of laminin 511 and laminin 521.

Supplementary Video 6

Time-lapse image series of KPC-1 PCCs adhering to a combination of laminin 511, laminin 521 and FN.

Supplementary Video 7

Time-lapse image series of KPC-1 PCCs adhering to FN.

Supplementary Video 8

Time-lapse image series of KPC-1 PCCs adhering to collagen-1.

Supplementary Video 9

Time-lapse image series of KPC-1 PCCs adhering to a non-coated glass surface.

Supplementary Video 10

3D reconstruction of a representative mPDO from Supplementary Fig. 12d.

Supplementary Video 11

3D reconstruction of a representative mPDO from Supplementary Fig. 12e.

Supplementary Video 12

Maximum intensity projection (MIPs) videos of co-cultures from Supplementary Fig. 25.

Supplementary Video 13

Maximum intensity projection (MIPs) videos of co-cultures from Supplementary Fig. 25.

Supplementary Video 14

Maximum intensity projection (MIPs) videos of co-cultures from Supplementary Fig. 25.

Supplementary Video 15

Maximum intensity projection (MIPs) videos of co-cultures from Supplementary Fig. 25.

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Below, C.R., Kelly, J., Brown, A. et al. A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids. Nat. Mater. 21, 110–119 (2022). https://doi.org/10.1038/s41563-021-01085-1

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