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Single luminal epithelial progenitors can generate prostate organoids in culture

Nature Cell Biology volume 16, pages 951–961 (2014)Cite this article

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Abstract

The intrinsic ability to exhibit self-organizing morphogenetic properties in ex vivo culture may represent a general property of tissue stem cells. Here we show that single luminal stem/progenitor cells can generate prostate organoids in a three-dimensional culture system in the absence of stroma. Organoids generated from CARNs (castration-resistant Nkx3.1-expressing cells) or normal prostate epithelia exhibit tissue architecture containing luminal and basal cells, undergo long-term expansion in culture and exhibit functional androgen receptor signalling. Lineage-tracing demonstrates that luminal cells are favoured for organoid formation and generate basal cells in culture. Furthermore, tumour organoids can initiate from CARNs after oncogenic transformation and from mouse models of prostate cancer, and can facilitate analyses of drug response. Finally, we provide evidence supporting the feasibility of organoid studies of human prostate tissue. Our studies underscore the progenitor properties of luminal cells, and identify in vitro approaches for studying prostate biology.

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Figure 1: Generation of prostate epithelial organoids from lineage-marked CARNs.
Figure 2: Growth and androgen-responsiveness of prostate organoids from normal prostate epithelium.
Figure 3: Lineage-tracing shows that luminal cells are favoured for generation of prostate organoids.
Figure 4: Tumour organoids can be generated from single transformed CARNs.
Figure 5: Modelling tumour phenotypes in organoid culture.
Figure 6: Modelling drug treatment response in organoid culture.

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Acknowledgements

We thank M. Kruithof-de Julio, M. Hanoun and P. Frenette for initial discussions about organoid culture, C. Sawyers and C. Abate-Shen for providing pathway inhibitors, C. Liu and the HICCC Flow Cytometry Shared Resource for flow-sorting, D. Sun for assistance with specimen acquisition, the HICCC Molecular Pathology Shared Resource for organoid sectioning and H&E staining, F. Talos for helpful comments on the culture protocol, D-E Parfitt for assistance with cell-picking, and C. Abate-Shen and F. Talos for insightful discussions and comments on the manuscript. This work was supported by postdoctoral fellowships from the DOD Prostate Cancer Research Program (C.W.C., M.S. and R.T.), by a Residency Research Award from the Urology Care Foundation (L.J.B.), and by grants from the National Institutes of Health (M.M.S.).

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  1. Chee Wai Chua, Maho Shibata and Ming Lei: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA

    Chee Wai Chua, Maho Shibata, Ming Lei, Roxanne Toivanen, Sarah K. Bergren & Michael M. Shen

  2. Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA

    Chee Wai Chua, Maho Shibata, Ming Lei, Roxanne Toivanen, Sarah K. Bergren & Michael M. Shen

  3. Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA

    Chee Wai Chua, Maho Shibata, Ming Lei, Roxanne Toivanen, Sarah K. Bergren & Michael M. Shen

  4. Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA

    Chee Wai Chua, Maho Shibata, Ming Lei, Roxanne Toivanen, LaMont J. Barlow, Sarah K. Bergren, Ketan K. Badani, James M. McKiernan, Mitchell C. Benson & Michael M. Shen

  5. Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA

    Hanina Hibshoosh

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Contributions

C.W.C. and M.L. developed the organoid culture protocol, C.W.C. and M.S. performed analyses of CARN-derived and normal prostate organoids, M.S. performed lineage-tracing studies, M.L. performed analyses of transformed CARN organoids and drug response, R.T. performed analyses of benign human prostate organoids, M.S. and C.W.C. analysed VCaP organoids, L.J.B. performed studies of tumour organoids from mouse models, and S.K.B. assisted with single-cell experiments and tissue grafts, K.K.B. and J.M.M. provided surgical specimens, and H.H. performed pathological analyses. C.W.C., M.S., M.L., R.T., L.J.B., M.C.B, H.H. and M.M.S. designed experiments, analysed data and wrote the manuscript.

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Correspondence to Chee Wai Chua, Maho Shibata, Ming Lei or Michael M. Shen.

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Integrated supplementary information

Supplementary Figure 1 Analysis of normal organoids during serial passaging.

(a–c) Bright-field images of organoids from normal prostate epithelium at passage 1 (a), passage 6 (b), and passage 13 (c). (d,e) Analysis of organoids at passage 3 shows normal expression of the basal marker p63 (arrowheads, d) and the luminal marker CK8 (d,e), as well as nuclear expression of AR (arrows, e); yellow arrow in d indicates intermediate cell that co-expresses p63 and CK8. Scale bars in d,e correspond to 50 μm and in a–c to 100 μm.

Supplementary Figure 2 Specificity of luminal and basal lineage-marking in prostate epithelium in vivo.

Sections from the anterior prostate of CK5-CreERT2; R26R-YFP mice (a), CK8-CreERT2; R26R-YFP mice (b), CK18-CreERT2; R26R-YFP mice (c), and CK18-CreERT2; R26R-Tomato mice (d) demonstrate specificity of basal marking (arrowheads, a) and luminal marking (arrows, b–d). Scale bars correspond to 100 μm.

Supplementary Figure 3 Generation of human prostate organoids.

(a–e) Establishment of organoids from benign human prostate specimens. (f–j) Generation of organoids from the VCaP prostate cancer cell line. (a,f) Bright-field images. (b,g) H&E staining. (c,h) Ki67 immunostaining; arrows indicate proliferating cells. (d) Most exterior cells in benign human organoids are CK8+p63+ cells (arrowheads), while many interior cells are CK8+ only (arrow). (e) Most cells in benign human organoids are AR+CK18+ cells (arrows). (i) VCaP organoids display immunostaining for CK18, but not p63. (j) VCaP organoids are strongly positive for both AR and CK8. Scale bars in b–e,g–j correspond to 50 μm, and in a,f correspond to 100 μm.

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Chua, C., Shibata, M., Lei, M. et al. Single luminal epithelial progenitors can generate prostate organoids in culture. Nat Cell Biol 16, 951–961 (2014). https://doi.org/10.1038/ncb3047

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