Identification and Targeting of Long-Term Tumor-Propagating Cells in Small Cell Lung Cancer
Nadine S. Jahchan,
Jing Shan Lim,
Becky Bola,
Karen Morris,
Garrett Seitz,
Kim Q. Tran,
Lei Xu,
Francesca Trapani,
Christopher J. Morrow,
Sandra Cristea,
Garry L. Coles,
Dian Yang,
Dedeepya Vaka,
Michael S. Kareta,
Julie George,
Pawel K. Mazur,
Thuyen Nguyen,
Wade C. Anderson,
Scott J. Dylla,
Fiona Blackhall,
Martin Peifer,
Caroline Dive,
Julien Sage
Affiliations
Nadine S. Jahchan
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Jing Shan Lim
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Becky Bola
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester and Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4BX, UK
Karen Morris
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester and Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4BX, UK
Garrett Seitz
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Kim Q. Tran
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Lei Xu
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Francesca Trapani
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester and Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4BX, UK
Christopher J. Morrow
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester and Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4BX, UK
Sandra Cristea
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Garry L. Coles
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Dian Yang
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Dedeepya Vaka
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Michael S. Kareta
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Julie George
Medical Faculty, Department of Translational Genomics, Center of Integrated Oncology Cologne–Bonn and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
Pawel K. Mazur
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Thuyen Nguyen
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Wade C. Anderson
Stemcentrx Inc., South San Francisco, CA 94080, USA
Scott J. Dylla
Stemcentrx Inc., South San Francisco, CA 94080, USA
Fiona Blackhall
Institute of Cancer Sciences, University of Manchester and Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4BX, UK
Martin Peifer
Medical Faculty, Department of Translational Genomics, Center of Integrated Oncology Cologne–Bonn and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
Caroline Dive
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester and Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4BX, UK
Julien Sage
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
Small cell lung cancer (SCLC) is a neuroendocrine lung cancer characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified a population of long-term tumor-propagating cells (TPCs) in a mouse model of SCLC. This population, marked by high levels of EpCAM and CD24, is also prevalent in human primary SCLC tumors. Murine SCLC TPCs are numerous and highly proliferative but not intrinsically chemoresistant, indicating that not all clinical features of SCLC are linked to TPCs. SCLC TPCs possess a distinct transcriptional profile compared to non-TPCs, including elevated MYC activity. Genetic and pharmacological inhibition of MYC in SCLC cells to non-TPC levels inhibits long-term propagation but not short-term growth. These studies identify a highly tumorigenic population of SCLC cells in mouse models, cell lines, and patient tumors and a means to target them in this most fatal form of lung cancer.
