Article

Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer

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Abstract

Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor with early dissemination and dismal prognosis, accounts for 15–20% of lung cancer cases and 200,000 deaths each year. Most cases are inoperable, and biopsies to investigate SCLC biology are rarely obtainable. Circulating tumor cells (CTCs), which are prevalent in SCLC, present a readily accessible 'liquid biopsy'. Here we show that CTCs from patients with either chemosensitive or chemorefractory SCLC are tumorigenic in immune-compromised mice, and the resultant CTC-derived explants (CDXs) mirror the donor patient's response to platinum and etoposide chemotherapy. Genomic analysis of isolated CTCs revealed considerable similarity to the corresponding CDX. Most marked differences were observed between CDXs from patients with different clinical outcomes. These data demonstrate that CTC molecular analysis via serial blood sampling could facilitate delivery of personalized medicine for SCLC. CDXs are readily passaged, and these unique mouse models provide tractable systems for therapy testing and understanding drug resistance mechanisms.

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Acknowledgements

We are indebted to the patients who agreed to donate their blood samples for this study. We thank R. Marais, N. Jones and D. Ogilvie for their constructive comments on the manuscript. We thank M. Dawson, M. Lancashire, S. Bramley, J. Halstead and J. Castle, who enumerated CTCs using CellSearch. We thank A. Jardine for administrative support and M. Greaves, our laboratory manager. This research was supported by Cancer Research UK via core funding to the Cancer Research UK Manchester Institute (C5759/A12328), the Manchester Experimental Cancer Medicine Centre (C1467/A15578), the Manchester Cancer Research Centre (A12197) and their Translational Research Award for 2012. Funding to support this work was also provided via the European Union CHEMORES FP6 (contract number LSHG-CT-2007-037665). R.L.M. and L.C. were supported by education grants from Cancer Research UK and AstraZeneca.

Author information

Author notes

    • Cassandra L Hodgkinson
    •  & Christopher J Morrow

    These authors contributed equally to this work.

    • Fiona Blackhall
    • , Ged Brady
    •  & Caroline Dive

    These authors jointly supervised this work.

Affiliations

  1. Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.

    • Cassandra L Hodgkinson
    • , Christopher J Morrow
    • , Robert L Metcalf
    • , Dominic G Rothwell
    • , Francesca Trapani
    • , Radoslaw Polanski
    • , Deborah J Burt
    • , Kathryn L Simpson
    • , Karen Morris
    • , Alastair Greystoke
    • , Paul Kelly
    • , Becky Bola
    • , Matthew G Krebs
    • , Jenny Antonello
    • , Mahmood Ayub
    • , Suzanne Faulkner
    • , Lynsey Priest
    • , Louise Carter
    • , Catriona Tate
    • , Ged Brady
    •  & Caroline Dive
  2. Computational Biology Support Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.

    • Yaoyong Li
    •  & Crispin J Miller
  3. Molecular Biology Core Facility, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.

    • Stuart D Pepper
  4. The Christie NHS Foundation Trust, Manchester, UK.

    • Daisuke Nonaka
    • , Alastair Greystoke
    •  & Fiona Blackhall
  5. Institute of Cancer Sciences, University of Manchester, Manchester, UK.

    • Alastair Greystoke
    •  & Fiona Blackhall
  6. RNA Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.

    • Crispin J Miller

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Contributions

C.L.H., P.K. and B.B. performed in vivo studies, F.T., R.P., K.L.S. and D.N. conducted histopathological examinations, D.G.R., D.J.B., S.D.P., A.G., J.A., M.G.K., M.A., L.C. and S.F. conducted the genomic analyses, Y.L., C.T., C.J. Miller and G.B. performed the bioinformatic analysis, K.M. oversaw CTC enumeration by CellSearch, R.L.M., L.C., L.P. and F.B. recruited and consented patients and collected blood samples, C.J. Morrow, C.J. Miller, G.B., F.B. and C.D. conceived and directed the study, interpreted the data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Caroline Dive.

Supplementary information

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