title: Single-cell analysis of lung adenocarcinoma cell lines reveals diverse expression patterns of individual cells invoked by a molecular target drug treatment.
abstract: BACKGROUND
  To understand the heterogeneous behaviors of individual cancer cells, it is essential to investigate gene expression levels as well as their divergence between different individual cells. Recent advances in next-generation sequencing-related technologies have enabled us to conduct a single-cell RNA-Seq analysis of a series of lung adenocarcinoma cell lines.
  
  
  RESULTS
  We analyze a total of 336 single-cell RNA-Seq libraries from seven cell lines. The results are highly robust regarding both average expression levels and the relative gene expression differences between individual cells. Gene expression diversity is characteristic depending on genes and pathways. Analyses of individual cells treated with the multi-tyrosine kinase inhibitor vandetanib reveal that, while the ribosomal genes and many other so-called house-keeping genes reduce their relative expression diversity during the drug treatment, the genes that are directly targeted by vandetanib, the EGFR and RET genes, remain constant. Rigid transcriptional control of these genes may not allow plastic changes of their expression with the drug treatment or during the cellular acquisition of drug resistance. Additionally, we find that the gene expression patterns of cancer-related genes are sometimes more diverse than expected based on the founder cells. Furthermore, we find that this diversity is occasionally latent in a normal state and initially becomes apparent after the drug treatment.
  
  
  CONCLUSIONS
  Characteristic patterns in gene expression divergence, which would not be revealed by transcriptome analysis of bulk cells, may also play important roles when cells acquire drug resistance, perhaps by providing a cellular reservoir for gene expression programs.
authors.affiliation: Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan. asuzuki@hgc.jp.
authors.forename: Ayako
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Division of TR, The Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, 277-8577, Japan. komatsus@east.ncc.go.jp.
authors.forename: Koutatsu
authors.initials: K
authors.lastname: Matsushima
authors.affiliation: Division of TR, The Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, 277-8577, Japan. hmakinos@east.ncc.go.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makinoshima
authors.affiliation: Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan. ssugano@k.u-tokyo.ac.jp.
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, 104-0045, Japan. tkkohno@ncc.go.jp.|Division of TR, The Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, 104-0045, Japan. tkkohno@ncc.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Division of TR, The Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, 277-8577, Japan. ktsuchih@east.ncc.go.jp.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tsuchihara
authors.affiliation: Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan. ysuzuki@hgc.jp.|Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan. ysuzuki@hgc.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020043:Genes, Essential; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods*; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D012313:RNA / Q000235:genetics; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D059467:Transcriptome
chemical_list: C088832:CCDC6 protein, human; D003598:Cytoskeletal Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012313:RNA; C512478:EGFR protein, human; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C452423:vandetanib