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The future of patient-derived xenografts in prostate cancer research

Nature Reviews Urology volume 20, pages 371–384 (2023)Cite this article

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Abstract

Patient-derived xenografts (PDXs) are generated by engrafting human tumours into mice. Serially transplantable PDXs are used to study tumour biology and test therapeutics, linking the laboratory to the clinic. Although few prostate cancer PDXs are available in large repositories, over 330 prostate cancer PDXs have been established, spanning broad clinical stages, genotypes and phenotypes. Nevertheless, more PDXs are needed to reflect patient diversity, and to study new treatments and emerging mechanisms of resistance. We can maximize the use of PDXs by exchanging models and datasets, and by depositing PDXs into biorepositories, but we must address the impediments to accessing PDXs, such as institutional, ethical and legal agreements. Through collaboration, researchers will gain greater access to PDXs representing diverse features of prostate cancer.

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Fig. 1: A summary of PDXs in large international collections.
Fig. 2: The design of expansion versus a 1 × 1 × 1 study experiments with PDXs.
Fig. 3: Modelling tumour heterogeneity with PDXS.
Fig. 4: The features of PDXs ideal for collaborative research.

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Acknowledgements

The authors thank the participants of the Virtual Prostate Cancer PDX Symposium series for sharing their views. They acknowledge the patients, clinical co-ordinators, clinicians and scientists who contribute to the establishment and maintenance of each of the collections of prostate cancer PDXs discussed in this Perspective. Authors from Monash University and the Peter MacCallum Cancer Centre thank members of the Melbourne Urological Research Alliance, kConFab, and CASCADE. Authors from the University of Washington/Fred Hutchinson Cancer Research Center would like to thank the patients who generously donated the tissue that made this research possible. The authors also thank J. Conner, M. Dalos, D. Sondheim and the Comparative Medicine Animal Caregivers for assistance with the LuCaP xenograft work. Additionally, they thank P. Lange, R. Vessella, F. Vakar-Lopez, M. Roudier, X. Zhang, B. Nghiem and the rapid autopsy teams and physicians in the Urology and Medical Oncology Departments at the University of Washington. The authors receive funding from the Movember Foundation Global Action Plan 1 PDX Project; US Department of Defense through the Prostate Cancer Research Program (W81XWH1810347, W81XWH1810348 and W81XWH1810349; opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense); the Movember Foundation (Global Action Plan 1); the Victorian Cancer Agency (MCRF15023, MCRF18017 and MCRF17005; CAPTIV Program); the National Health and Medical Research Council, Australia (1102752, 1138242, 1140222, 1156570, 1185616, 2011033 and 2011391); the Rotary Club of Manningham; RULE Prostate Cancer and the EJ Whitten Foundation; the Peter and Lyndy White Foundation; TissuPath Pathology; the Peter MacCallum Cancer Foundation; the Pacific Northwest Prostate Cancer SPORE (P50CA97186); the Department of Defense Prostate Cancer Biorepository Network (W81XWH-14-2-0183); CDMRP award W81XWH-21-1-0264; National Institute of Health/National Cancer Institute (P01 CA163227, R01CA234715, U01 CA224044-03, U54 CA233223, SBIR Phase I HHSN26120700015C); the Baylor College of Medicine, Minority PDX Development and Trial Center: Baylor College of Medicine and MD Anderson Cancer Center Collaboration on Mechanistic Studies to Dissect and Combat Health Disparities in Cancer, SBIR Phase II/Mimetas US, Inc); the Prostate Cancer Foundation; the Institute for Prostate Cancer Research; the Richard M. Lucas Foundation; the Craig Watjen Memorial Fund; Fond’Action contre le cancer (Young Investigator Award 2020); the Department of Surgery of the University Hospital Basel; the David H. Koch Center for Applied Research in Genitourinary Cancers at MD Anderson; the Canadian Institutes of Health Research (141635, 144159, 153081 and 173338); the Terry Fox Research Institute (1062); the Mitacs Accelerate Program (IT10125, IT06414, IT12387 and IT14958); and the EU Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant (721746; ‘TRANSPOT’).

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Authors and Affiliations

  1. Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia

    Mitchell G. Lawrence, Georgia B. Cuffe, Ashlee K. Clark, Laura H. Porter & Gail P. Risbridger

  2. Melbourne Urological Research Alliance, Monash Biomedicine Discovery Institute, Clayton, Victoria, Australia

    Mitchell G. Lawrence, Renea A. Taylor & Gail P. Risbridger

  3. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Mitchell G. Lawrence, Renea A. Taylor, David L. Goode & Gail P. Risbridger

  4. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

    Mitchell G. Lawrence, Renea A. Taylor, David L. Goode & Gail P. Risbridger

  5. Cabrini Institute, Cabrini Health, Malvern, Victoria, Australia

    Mitchell G. Lawrence, Renea A. Taylor & Gail P. Risbridger

  6. Department of Physiology, Monash University, Clayton, Victoria, Australia

    Renea A. Taylor

  7. Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Lisa S. Ang & Peter S. Nelson

  8. Department of Urology, Radboud University Medical Center, Nijmegen, Netherlands

    Ashlee K. Clark & Jack A. Schalken

  9. Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland

    Clémentine Le Magnen

  10. Department of Urology, University Hospital Basel, Basel, Switzerland

    Clémentine Le Magnen

  11. Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland

    Clémentine Le Magnen

  12. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Nora M. Navone

  13. David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Nora M. Navone

  14. Vancouver Prostate Centre, Vancouver, British Columbia, Canada

    Yuzhuo Wang

  15. Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Yuzhuo Wang

  16. Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada

    Yuzhuo Wang

  17. Department of Urology, Erasmus MC Cancer Institute, Rotterdam, Netherlands

    Wytske M. van Weerden

  18. Department of Urology, University of Washington, Seattle, WA, USA

    Eva Corey & Peter S. Nelson

  19. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, MD, USA

    John T. Isaacs

  20. Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    John T. Isaacs

  21. Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    John T. Isaacs

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Contributions

G.P.R., R.A.T. and M.G.L. researched data for the article, made a substantial contribution to discussion of content and wrote the article. G.B.C. wrote the article and made a substantial contribution to discussion of content. E.C., J.T.I. and P.S.N. made a substantial contribution to discussion of content. All authors reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Mitchell G. Lawrence or Gail P. Risbridger.

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Competing interests

G.P.R., R.A.T. and M.G.L. have been involved in research collaborations with AstraZeneca and Pfizer. W.M.v.W. has been involved in research collaborations with Bayer. E.C. has received research funding under institutional sponsored research agreements from AbbVie, Bayer Pharmaceuticals, Forma Pharmaceutics Foghorn, Gilead, GSK, Janssen Research and Development, KronosBio, MacroGenics and Sanofi. P.S.N. has been a paid consultant to Astellas, Bristol Myers Squibb, Janssen and Pfizer for work unrelated to the present study. The remaining authors declare no competing interests.

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Nature Reviews Urology thanks Gabri van der Pluijm, Alastair Lamb and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Jackson Laboratory: https://www.jax.org

Living Tumour Laboratory: http://www.livingtumorlab.com

Patient-Derived Models Repository: https://pdmr.cancer.gov

PDXFinder: https://www.pdxfinder.org

PDXNet: https://www.pdxnetwork.org

Supplementary information

Glossary

3D scaffolds

Support structures made from natural or synthetic materials used for in vitro cell culture, aiming to mimic the architecture and/or biomechanical features of tissue.

Conditionally reprogrammed cells

In vitro cultures of normal or tumour epithelial cells grown on a feeder layer of irradiated feeder cells (typically mouse 3T3 cells).

Ex vivo slice cultures

Chopped, minced or sliced pieces of tissue submerged in culture media or grown on top of sponges or mesh inserts. Also referred to as explants.

Hydrogels

Synthetic or naturally occurring materials that form 3D matrices to support the growth of cells, including organoids, typically having a more defined composition than Matrigel.

Matrigel

A solution of extracellular matrix proteins secreted by mouse Engelbreth–Holm–Swarm sarcoma cells often used to grow organoid cultures.

Microwells

Arrays of small wells (approximately 150 per cm2) fabricated from silicon or other materials, used to grow separate clusters of cells within a larger tissue culture plate.

Organoids

Clusters of cells grown in suspension or embedded in a matrix, rather than cultured in two dimensions (typically monocultures of tumour cells for prostate cancer).

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Lawrence, M.G., Taylor, R.A., Cuffe, G.B. et al. The future of patient-derived xenografts in prostate cancer research. Nat Rev Urol 20, 371–384 (2023). https://doi.org/10.1038/s41585-022-00706-x

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