Generating human prostate cancer organoids from leukapheresis enriched circulating tumour cells

Lisanne Mout, Lisanne F. van Dessel, Jaco Kraan, Anouk C. de Jong, Rui P.L. Neves, Sigrun Erkens-Schulze, Corine M. Beaufort, Anieta M. Sieuwerts, Job van Riet, Thomas L.C. Woo, Ronald de Wit, Stefan Sleijfer, Paul Hamberg, Yorick Sandberg, Peter A.W. te Boekhorst, Harmen J.G. van de Werken, John W.M. Martens, Nikolas H. Stoecklein, Wytske M. van Weerden, Martijn P. Lolkema*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: Circulating tumour cell (CTC)–derived organoids have the potential to provide a powerful tool for personalised cancer therapy but are restrained by low CTC numbers provided by blood samples. Here, we used diagnostic leukapheresis (DLA) to enrich CTCs from patients with metastatic prostate cancer (mPCa) and explored whether organoids provide a platform for ex vivo treatment modelling. Methods: We prospectively screened 102 patients with mPCa and performed DLA in 40 patients with ≥5 CTCs/7.5 mL blood. We enriched CTCs from DLA using white blood cell (WBC) depletion alone or combined with EpCAM selection. The enriched CTC samples were cultured in 3D to obtain organoids and used for downstream analyses. Results: The DLA procedure resulted in a median yield of 5312 CTCs as compared with 22 CTCs in 7.5 mL of blood. Using WBC depletion, we recovered 46% of the CTCs, which reduced to 12% with subsequent EpCAM selection. From the isolated and enriched CTC samples, organoid expansion succeeded in 35%. Successful organoid cultures contained significantly higher CTC numbers at initiation. Moreover, we performed treatment modelling in one organoid cell line and identified substantial tumour heterogeneity in CTCs using single cell DNA sequencing. Conclusions: DLA is an efficient method to enrich CTCs, although the modest success rate of culturing CTCs precludes large scale clinical application. Our data do suggest that DLA and subsequent processing provides a rich source of viable tumour cells. Therefore, DLA offers a promising alternative to biopsy procedures to obtain sufficient number of tumour cells to study sequential samples in patients with mPCa. Trial registration number: NL6019.

Original languageEnglish
Pages (from-to)179-189
Number of pages11
JournalEuropean Journal of Cancer
Volume150
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
Martijn Lolkema has an advisory role and/or received speaker fees from; Incyte, Amgen, Janssen Cilag B.V., Bayer, Servier, Roche, Pfizer Sanofi Aventis Netherlands BV, Astellas and has received (Institutional) research funding from Sanofi, JnJ, Merck and Astellas.

Funding Information:
Wytske van Weerden has received (Institutional) research funding from —Sanofi, Janssen Pharmaceuticals and Bayer.Rui P.L.

Funding Information:
The authors thank Fred Guurink for his philanthropic support of our study; Katharina Raba and Jean Helmijr for their technical support with the single cell selection. The authors thank Elena Martens-Uzunova for carefully reading the manuscript. The authors thank Cancer Genomics Netherlands for financial support of coauthor A.S. The authors thank Wouter Karthaus and Jack Schalkes for providing us with the MSK-PCa1 and MSK-PCa2 organoid cell lines. The authors also thank the Hartwig Medical Foundation (www.hartwigmedicalfoundation.nl) and the Center of Personalised Cancer Treatment (www.CPCT.nl) for their help with generating and analyzing the WGS data.

Funding Information:
This work was supported by KWF-Alpe d’HuZes project [EMCR 2015–8037] and in parts by a grant from the Dutch Association of Medical Oncology (NVMO).

Publisher Copyright:
© 2021 The Author(s)

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