Mouse Model for ROS1-Rearranged Lung Cancer

Yasuhito Arai, Yasushi Totoki, Hiroyuki Takahashi, Hiromi Nakamura, Natsuko Hama, Takashi Kohno, Koji Tsuta, Akihiko Yoshida, Hisao Asamura, Michihiro Mutoh, Fumie Hosoda, Hitoshi Tsuda, Tatsuhiro Shibata

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC). However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22-q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer.

Original languageEnglish
Article numbere56010
JournalPLoS One
Volume8
Issue number2
DOIs
Publication statusPublished - 2013 Feb 13
Externally publishedYes

Fingerprint

Gene Fusion
lung neoplasms
Non-Small Cell Lung Carcinoma
gene fusion
Lung Neoplasms
phosphotransferases (kinases)
Phosphotransferases
Fusion reactions
animal models
lungs
Lung
Carcinogenesis
adenocarcinoma
carcinogenesis
Genes
Alveolar Epithelial Cells
Receptor Protein-Tyrosine Kinases
cells
Growth
Oncogenes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Arai, Y., Totoki, Y., Takahashi, H., Nakamura, H., Hama, N., Kohno, T., ... Shibata, T. (2013). Mouse Model for ROS1-Rearranged Lung Cancer. PLoS One, 8(2), [e56010]. https://doi.org/10.1371/journal.pone.0056010

Mouse Model for ROS1-Rearranged Lung Cancer. / Arai, Yasuhito; Totoki, Yasushi; Takahashi, Hiroyuki; Nakamura, Hiromi; Hama, Natsuko; Kohno, Takashi; Tsuta, Koji; Yoshida, Akihiko; Asamura, Hisao; Mutoh, Michihiro; Hosoda, Fumie; Tsuda, Hitoshi; Shibata, Tatsuhiro.

In: PLoS One, Vol. 8, No. 2, e56010, 13.02.2013.

Research output: Contribution to journalArticle

Arai, Y, Totoki, Y, Takahashi, H, Nakamura, H, Hama, N, Kohno, T, Tsuta, K, Yoshida, A, Asamura, H, Mutoh, M, Hosoda, F, Tsuda, H & Shibata, T 2013, 'Mouse Model for ROS1-Rearranged Lung Cancer', PLoS One, vol. 8, no. 2, e56010. https://doi.org/10.1371/journal.pone.0056010
Arai Y, Totoki Y, Takahashi H, Nakamura H, Hama N, Kohno T et al. Mouse Model for ROS1-Rearranged Lung Cancer. PLoS One. 2013 Feb 13;8(2). e56010. https://doi.org/10.1371/journal.pone.0056010
Arai, Yasuhito ; Totoki, Yasushi ; Takahashi, Hiroyuki ; Nakamura, Hiromi ; Hama, Natsuko ; Kohno, Takashi ; Tsuta, Koji ; Yoshida, Akihiko ; Asamura, Hisao ; Mutoh, Michihiro ; Hosoda, Fumie ; Tsuda, Hitoshi ; Shibata, Tatsuhiro. / Mouse Model for ROS1-Rearranged Lung Cancer. In: PLoS One. 2013 ; Vol. 8, No. 2.
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