title: Single-cell mRNA sequencing identifies subclonal heterogeneity in anti-cancer drug responses of lung adenocarcinoma cells.
abstract: BACKGROUND
  Intra-tumoral genetic and functional heterogeneity correlates with cancer clinical prognoses. However, the mechanisms by which intra-tumoral heterogeneity impacts therapeutic outcome remain poorly understood. RNA sequencing (RNA-seq) of single tumor cells can provide comprehensive information about gene expression and single-nucleotide variations in individual tumor cells, which may allow for the translation of heterogeneous tumor cell functional responses into customized anti-cancer treatments.
  
  
  RESULTS
  We isolated 34 patient-derived xenograft (PDX) tumor cells from a lung adenocarcinoma patient tumor xenograft. Individual tumor cells were subjected to single cell RNA-seq for gene expression profiling and expressed mutation profiling. Fifty tumor-specific single-nucleotide variations, including KRAS(G12D), were observed to be heterogeneous in individual PDX cells. Semi-supervised clustering, based on KRAS(G12D) mutant expression and a risk score representing expression of 69 lung adenocarcinoma-prognostic genes, classified PDX cells into four groups. PDX cells that survived in vitro anti-cancer drug treatment displayed transcriptome signatures consistent with the group characterized by KRAS(G12D) and low risk score.
  
  
  CONCLUSIONS
  Single-cell RNA-seq on viable PDX cells identified a candidate tumor cell subgroup associated with anti-cancer drug resistance. Thus, single-cell RNA-seq is a powerful approach for identifying unique tumor cell-specific gene expression profiles which could facilitate the development of optimized clinical anti-cancer strategies.
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. kimqtae@snu.ac.kr.|Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, South Korea. kimqtae@snu.ac.kr.
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Kim
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea. nsproper@naver.com.|Department of Urology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea. nsproper@naver.com.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. nsproper@naver.com.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. haeock.lee@samsung.com.|Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea. haeock.lee@samsung.com.
authors.forename: Hae-Ock
authors.initials: HO
authors.lastname: Lee
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. sang.cheol.kim@samsung.com.
authors.forename: Sang Cheol
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea. yunjee.seo@gmail.com.|Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea. yunjee.seo@gmail.com.
authors.forename: Yun Jee
authors.initials: YJ
authors.lastname: Seo
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. cws1021@skku.edu.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. cws1021@skku.edu.
authors.forename: Woosung
authors.initials: W
authors.lastname: Chung
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. smflsdkdl@snu.ac.kr.|Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, South Korea. smflsdkdl@snu.ac.kr.
authors.forename: Hye Hyeon
authors.initials: HH
authors.lastname: Eum
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea. nsnam@skku.edu.|Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea. nsnam@skku.edu.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. nsnam@skku.edu.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA. junhyong@sas.upenn.edu.|Penn Program in Single Cell Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA. junhyong@sas.upenn.edu.
authors.forename: Junhyong
authors.initials: J
authors.lastname: Kim
authors.affiliation: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea. kmjoo@skku.edu.|Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea. kmjoo@skku.edu.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. kmjoo@skku.edu.
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. woongyang.park@samsung.com.|Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea. woongyang.park@samsung.com.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. woongyang.park@samsung.com.
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010641:Phenotype; D012333:RNA, Messenger / Q000737:chemistry; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger