TY - JOUR
T1 - Lung adenocarcinoma mouse models based on orthotopic transplantation of syngeneic tumor-initiating cells expressing EpCAM, SCA-1, and Ly6d
AU - Semba, Takashi
AU - Sato, Ryo
AU - Kasuga, Akiyoshi
AU - Suina, Kentaro
AU - Shibata, Tatsuhiro
AU - Kohno, Takashi
AU - Suzuki, Makoto
AU - Saya, Hideyuki
AU - Arima, Yoshimi
N1 - Funding Information:
Funding: This work was supported by Translational Research Network Program, Research on Applying Health Technology, and Research on Rare and Intractable Diseases grants from the Japan Agency for Medical Research and Development to H.S., as well as by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (KAKENHI 22130007 to H.S., KAKENHI 20K08968 to Y.A.).
Funding Information:
2.2. Expansion of Oncogene-Transformed Lung Epithelial Cells Supported by Cdkn2a Knockout
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85098281542&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098281542&partnerID=8YFLogxK
U2 - 10.3390/cancers12123805
DO - 10.3390/cancers12123805
M3 - Article
AN - SCOPUS:85098281542
SN - 2072-6694
VL - 12
SP - 1
EP - 18
JO - Cancers
JF - Cancers
IS - 12
M1 - 3805
ER -