Ex Vivo Expansion and Drug Sensitivity Profiling of Circulating Tumor Cells from Patients with Small Cell Lung Cancer

  • Cancers (Basel). 2020 Nov 16;12(11):3394. doi: 10.3390/cancers12113394.
Hsin-Lun Lee  1  2  3 ,  Jeng-Fong Chiou  1  2  3  4 ,  Peng-Yuan Wang  5  6 ,  Long-Sheng Lu  1  4  7  8 ,  Chia-Ning Shen  9  10 ,  Han-Lin Hsu  11  12 ,  Thierry Burnouf  7  8 ,  Lai-Lei Ting  1 ,  Pai-Chien Chou  13  14 ,  Chi-Li Chung  13  15 ,  Kai-Ling Lee  13 ,  Her-Shyong Shiah  16  17 ,  Yen-Lin Liu  2  4  18  19 ,  Yin-Ju Chen  1  4  7  8
Affiliations
  • 1. Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan.
  • 2. Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan.
  • 3. Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 4. TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 5. Shenzhen Key Laboratory of Biomimetic Materials and Cellular Immunomodulation, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, China.
  • 6. Department of Chemistry and Biotechnology, Swinburne University of Technology, Hawthorn, VIC 3122, Australia.
  • 7. Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan.
  • 8. International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan.
  • 9. Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
  • 10. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 11. Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11600, Taiwan.
  • 12. School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 13. Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan.
  • 14. Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 15. Division of Thoracic Medicine, Department of Internal Medicine, School of Medicine and School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 16. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
  • 17. Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan.
  • 18. Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 19. Department of Pediatrics, Taipei Medical University Hospital, Taipei 11031, Taiwan.
PMID: 33207745 DOI: 10.3390/cancers12113394
Abstract

Small cell lung Cancer (SCLC) represents one of the most aggressive malignancies among Cancer types. Not only tumor sample availability is limited, but also the ability for tumor cells to rapidly acquire drug resistance are the rate-limiting bottlenecks for overall survival in current clinical settings. A liquid biopsy capable of capturing and enriching circulating tumor cells (CTCs), together with the possibility of drug screening, is a promising solution. Here, we illustrate the development of a highly efficient ex vivo CTC expansion system based on binary colloidal crystals substrate. Clinical samples were enrolled from 22 patients with SCLC in the study. The CTCs were enriched and expanded from the collected peripheral blood samples. Expanded cells were analyzed for protein expression and observed for drug sensitivity with the use of immunofluorescence and ATP titer evaluation, respectively. Successful CTC spheroid proliferation was established after 4 weeks within 82% of all the collected peripheral blood samples from enrolled patients. Upon immunofluorescence analysis, the enriched cells showed positive markers for EpCAM, TTF-1, synaptophysin and negative for CD45. Additionally, the expanded CTCs demonstrated marked heterogeneity in the expression of E-cadherin and N-Cadherin. In a preliminary case series, the drug sensitivity of patient-derived CTC to cisplatin and etoposide was studied to see the correlation with the corresponding therapeutic outcome. In conclusion, our study demonstrates that it is possible to efficiently expand CTCs from SCLC within a clinically relevant time frame; the biomarker information generated from enriched CTCs can assist the selection of effective drugs and improve disease outcome.

Keywords
circulating tumor cells; liquid biopsy; personalized medicine; primary cell culture; small cell lung cancer.
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