Lung adenocarcinoma mouse models based on orthotopic transplantation of syngeneic tumor-initiating cells expressing EpCAM, SCA-1, and Ly6d

Takashi Semba, Ryo Sato, Akiyoshi Kasuga, Kentaro Suina, Tatsuhiro Shibata, Takashi Kohno, Makoto Suzuki, Hideyuki Saya, Yoshimi Arima

Research output: Contribution to journalArticlepeer-review

Abstract

Somatic mutations in EGFR and KRAS as well as chromosome rearrangements affecting ALK, ROS1, and RET have been identified in human lung adenocarcinoma (LUAD). We here developed organoid-based orthotopic and syngeneic mouse models for studies of the pathogenesis and treatment of LUAD. We isolated EpCAM-positive epithelial cells from mouse lungs and cultured them as organoids to maintain epithelial stem cell properties. These cells were transformed by KRAS(G12V) or EML4-ALK and then transplanted via the trachea into the lungs of the syngeneic mice, where they formed tumors that expressed the lung lineage marker TTF-1 and which closely recapitulated the pathology of human LUAD. Treatment with crizotinib suppressed the growth of tumors formed by the EML4-ALK–expressing lung epithelial cells in a subcutaneous transplantation model. Organoid culture of normal lung epithelial cells resulted in enrichment of EpCAM+SCA-1(Ly6a)+ cells as well as in that of cells expressing another member of the Ly6 protein family, Ly6d, which was found to be required for the growth of the LUAD-initiating cells expressing KRAS(G12V) or EML4-ALK. We also found that a high expression level of LY6D was associated with poor prognosis in human LUAD. Our results thus suggest that LY6D is a potential lung cancer stem cell marker.

Original languageEnglish
Article number3805
Pages (from-to)1-18
Number of pages18
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished - 12-2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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