Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma
Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma
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DOI：
10.1016/j.celrep.2023.112212
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发表时间：
2023-03-06
期刊：
影响因子：
8.8
通讯作者：
Sato, Toshiro
中科院分区：
文献类型：
--
作者：
Ebisudani, Toshiki;Hamamoto, Junko;Sato, Toshiro
人肺癌是一组具有不同组织学和分子特征的肿瘤。为了建立一个覆盖这一广泛疾病谱的临床前平台，我们从多个来源获得了肺癌标本，包括痰液和循环肿瘤细胞，并生成了一个由43行患者来源的肺癌类器官组成的活生物库。类器官概括了原始肿瘤的组织学和分子标志。小生境因子依赖性表型筛选显示肺腺癌中EGFR突变与Wnt配体无关。肺泡类器官的基因工程揭示了EGFR-RAS信号传导的组成性激活提供了Wnt独立性。无论EGFR信号突变如何，肺泡身份基因NKX 2 -1的缺失都赋予Wnt依赖性。对Wnt靶向治疗的敏感性可以通过NKX 2 -1的表达状态来分层。我们的研究结果突出了表型驱动的类器官筛选和工程设计用于制造治疗策略以对抗癌症的潜力。
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 mul-tiple 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 mu-tations 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 stra-tegies to combat cancer.