Plasticity of circulating tumor cells in small cell lung cancer

Jiyoun Seo; Mihir Kumar; Jeremy Mason; Fiona Blackhall; Nicholas Matsumoto; Caroline Dive; James Hicks; Peter Kuhn; Stephanie N Shishido

doi:10.1038/s41598-023-38881-5

Plasticity of circulating tumor cells in small cell lung cancer

Sci Rep. 2023 Jul 21;13(1):11775. doi: 10.1038/s41598-023-38881-5.

Authors

Jiyoun Seo¹, Mihir Kumar¹, Jeremy Mason^{1

2

3}, Fiona Blackhall⁴, Nicholas Matsumoto¹, Caroline Dive^{5

6}, James Hicks^{1

7}, Peter Kuhn^{8

9

10

11

12

13}, Stephanie N Shishido¹⁴

Affiliations

¹ Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, 90089, USA.
² Institute of Urology, Catherine & Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
³ Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.
⁴ Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
⁵ Cancer Research UK Lung Cancer Centre of Excellence, University of Manchester and University College London, Manchester, UK.
⁶ CRUK Manchester Institute Cancer Biomarker Centre, University of Manchester, Manchester, UK.
⁷ Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
⁸ Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, 90089, USA. pkuhn@usc.edu.
⁹ Institute of Urology, Catherine & Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. pkuhn@usc.edu.
¹⁰ Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA. pkuhn@usc.edu.
¹¹ Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA, 90089, USA. pkuhn@usc.edu.
¹² Department of Aerospace and Mechanical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, 90089, USA. pkuhn@usc.edu.
¹³ Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, 90089, USA. pkuhn@usc.edu.
¹⁴ Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, 90089, USA. sshishid@usc.edu.

Abstract

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with low five-year survival rates. Recently described molecular phenotypes of SCLC exhibit differential vulnerabilities heralding potential for stratified treatment. Whilst tumor biopsy in SCLC is challenging, circulating tumor cells in the liquid biopsy are prevalent and can be repeatedly sampled accommodating the dynamic plasticity of SCLC phenotypes. The aim of this study was to characterize the heterogeneity of rare circulating cells with confirmed tumor origin and to explore a liquid biopsy approach for future clinical trials of targeted therapies. This study applied the 3rd generation of a previously validated direct imaging platform to 14 chemo-naive SCLC patients and 10 non-cancerous normal donor (ND) samples. Phenotypic heterogeneity of circulating rare cells in SCLC was observed and a patient-level classification model was established to stratify SCLC patients from non-cancerous donors. Eight rare cell groups, with combinations of epithelial, endothelial, and mesenchymal biomarker expression patterns, were phenotypically characterized. The single-cell genomic analysis confirmed the cancer cell plasticity in every rare cell group harboring clonal genomic alterations. This study shows rare cell heterogeneity and confirms cellular plasticity in SCLC providing a valuable resource for better opportunities to discover novel therapeutic targets in SCLC.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aggression
Humans
Lung Neoplasms* / genetics
Neoplastic Cells, Circulating*
Neuroendocrine Tumors*
Small Cell Lung Carcinoma* / genetics

Abstract

Publication types

MeSH terms

Grants and funding