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Jun 19, 2015;16 127.

Single-cell mRNA sequencing identifies subclonal heterogeneity in anti-cancer drug responses of lung adenocarcinoma cells.

Kyu-Tae Kim, Hye Won Lee, Hae-Ock Lee, Sang Cheol Kim, Yun Jee Seo, Woosung Chung, Hye Hyeon Eum, Do-Hyun Nam, Junhyong Kim, Kyeung Min Joo, Woong-Yang Park
Author Information
  1. Kyu-Tae Kim: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. kimqtae@snu.ac.kr.
  2. Hye Won Lee: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea. nsproper@naver.com.
  3. Hae-Ock Lee: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. haeock.lee@samsung.com.
  4. Sang Cheol Kim: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. sang.cheol.kim@samsung.com.
  5. Yun Jee Seo: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea. yunjee.seo@gmail.com.
  6. Woosung Chung: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. cws1021@skku.edu.
  7. Hye Hyeon Eum: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. smflsdkdl@snu.ac.kr.
  8. Do-Hyun Nam: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea. nsnam@skku.edu.
  9. Junhyong Kim: Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA. junhyong@sas.upenn.edu.
  10. Kyeung Min Joo: Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea. kmjoo@skku.edu.
  11. Woong-Yang Park: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. woongyang.park@samsung.com.
PMID: 26084335 DOI: 10.1186/s13059-015-0692-3

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.

Associated Data

GEO | GSE69405

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MeSH Term

Adenocarcinoma
Adenocarcinoma of Lung
Animals
Antineoplastic Agents
Drug Resistance, Neoplasm
Gene Expression Profiling
Genetic Heterogeneity
Humans
Lung Neoplasms
Male
Mice
Middle Aged
Phenotype
RNA, Messenger
Sequence Analysis, RNA
Single-Cell Analysis
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Chemicals

Antineoplastic Agents
RNA, Messenger
Journal Article Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000194 (Single-cell RNA sequencing of lung adenocarcinoma patient-derived cells)
GEN: GEND000195 (Single-cell RNA sequencing of lung adenocarcinoma patient-derived cells)

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