Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma

Toshiki Ebisudani, Junko Hamamoto, Kazuhiro Togasaki, Akifumi Mitsuishi, Kai Sugihara, Taro Shinozaki, Takahiro Fukushima, Kenta Kawasaki, Takashi Seino, Mayumi Oda, Hikaru Hanyu, Kohta Toshimitsu, Katsura Emoto, Yuichiro Hayashi, Keisuke Asakura, Todd A. Johnson, Hideki Terai, Shinnosuke Ikemura, Ichiro Kawada, Makoto IshiiTomoyuki Hishida, Hisao Asamura, Kenzo Soejima, Hidewaki Nakagawa, Masayuki Fujii, Koichi Fukunaga, Hiroyuki Yasuda, Toshiro Sato

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Human lung cancer is a constellation of tumors with various histological and molecular properties. To build a preclinical platform that covers this broad disease spectrum, we obtained lung cancer specimens from multiple sources, including sputum and circulating tumor cells, and generated a living biobank consisting of 43 lines of patient-derived lung cancer organoids. The organoids recapitulated the histological and molecular hallmarks of the original tumors. Phenotypic screening of niche factor dependency revealed that EGFR mutations in lung adenocarcinoma are associated with the independence from Wnt ligands. Gene engineering of alveolar organoids reveals that constitutive activation of EGFR-RAS signaling provides Wnt independence. Loss of the alveolar identity gene NKX2-1 confers Wnt dependency, regardless of EGFR signal mutation. Sensitivity to Wnt-targeting therapy can be stratified by the expression status of NKX2-1. Our results highlight the potential of phenotype-driven organoid screening and engineering for the fabrication of therapeutic strategies to combat cancer.

Original languageEnglish
Article number112212
JournalCell Reports
Volume42
Issue number3
DOIs
Publication statusPublished - 2023 Mar 28

Keywords

  • CP: Cancer
  • CP: Stem cell research
  • gene editing
  • lung cancer organoids
  • mucinous adenocarcinoma
  • stem cell niche

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology

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