title: Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer.
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.
authors.affiliation: 1] Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK. [2].
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Hodgkinson
authors.affiliation: 1] Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK. [2].
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morrow
authors.affiliation: Computational Biology Support Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Yaoyong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Metcalf
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Rothwell
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Trapani
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Polanski
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Burt
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Simpson
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Morris
authors.affiliation: Molecular Biology Core Facility, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Pepper
authors.affiliation: The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nonaka
authors.affiliation: 1] Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK. [2] The Christie NHS Foundation Trust, Manchester, UK. [3] Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Alastair
authors.initials: A
authors.lastname: Greystoke
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Kelly
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Becky
authors.initials: B
authors.lastname: Bola
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Krebs
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Antonello
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ayub
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Faulkner
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Priest
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Carter
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Catriona
authors.initials: C
authors.lastname: Tate
authors.affiliation: 1] Computational Biology Support Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK. [2] RNA Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Crispin J
authors.initials: CJ
authors.lastname: Miller
authors.affiliation: 1] The Christie NHS Foundation Trust, Manchester, UK. [2] Institute of Cancer Sciences, University of Manchester, Manchester, UK. [3].
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.affiliation: 1] Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK. [2].
authors.forename: Ged
authors.initials: G
authors.lastname: Brady
authors.affiliation: 1] Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK. [2].
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000473:pathology; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor