Papers

Peer-reviewed International journal
Oct 15, 2021

Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression.

International journal of cancer
  • Akihiro Miura
  • Daisuke Yamada
  • Masahiro Nakamura
  • Shuta Tomida
  • Dai Shimizu
  • Yan Jiang
  • Tomoka Takao
  • Hiromasa Yamamoto
  • Ken Suzawa
  • Kazuhiko Shien
  • Masaomi Yamane
  • Masakiyo Sakaguchi
  • Shinichi Toyooka
  • Takeshi Takarada
  • Display all

Volume
149
Number
8
First page
1593
Last page
1604
Language
English
Publishing type
Research paper (scientific journal)
DOI
10.1002/ijc.33713

Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2-hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2-hiPSCs, which expressed NKX2-1/TTF-1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2-like cells. HLOs that overexpressed HER2 transformed to tumor-like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2-hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue-like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC-derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression.

Link information
DOI
https://doi.org/10.1002/ijc.33713
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/34152598
ID information
  • DOI : 10.1002/ijc.33713
  • Pubmed ID : 34152598

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