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Br J Pharmacol. 2019 Feb;176(3):436-450. doi: 10.1111/bph.14542. Epub 2018 Dec 13.

Ex vivo culture of cells derived from circulating tumour cell xenograft to support small cell lung cancer research and experimental therapeutics.

Author information

1
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Macclesfield, UK.
2
RNA Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
3
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
4
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
5
Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
6
Faculty of Biology, Medicine and Health Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
7
Institute of Cancer Sciences, University of Manchester and Christie NHS Foundation Trust, Manchester, UK.
8
Cancer Research UK Lung Cancer Centre of Excellence, Manchester, UK.

Abstract

BACKGROUND AND PURPOSE:

Small cell lung cancer (SCLC) is an aggressive disease with median survival of <2 years. Tumour biopsies for research are scarce, especially from extensive-stage patients, with repeat sampling at disease progression rarely performed. We overcame this limitation for relevant preclinical models by developing SCLC circulating tumour cell derived explants (CDX), which mimic the donor tumour pathology and chemotherapy response. To facilitate compound screening and identification of clinically relevant biomarkers, we developed short-term ex vivo cultures of CDX tumour cells.

EXPERIMENTAL APPROACH:

CDX tumours were disaggregated, and the human tumour cells derived were cultured for a maximum of 5 weeks. Phenotypic, transcriptomic and pharmacological characterization of these cells was performed.

KEY RESULTS:

CDX cultures maintained a neuroendocrine phenotype, and most changes in the expression of protein-coding genes observed in cultures, for up to 4 weeks, were reversible when the cells were re-implanted in vivo. Moreover, the CDX cultures exhibited a similar sensitivity to chemotherapy compared to the corresponding CDX tumour in vivo and were able to predict in vivo responses to therapeutic candidates.

CONCLUSIONS AND IMPLICATIONS:

Short-term cultures of CDX provide a tractable platform to screen new treatments, identify predictive and pharmacodynamic biomarkers and investigate mechanisms of resistance to better understand the progression of this recalcitrant tumour.

PMID:
30427531
PMCID:
PMC6329630
[Available on 2020-02-01]
DOI:
10.1111/bph.14542

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