Regenerative lineages and immune-mediated pruning in lung cancer metastasis
Regenerative lineages and immune-mediated pruning in lung cancer metastasis
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DOI：
10.1038/s41591-019-0750-6
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发表时间：
2020-02-10
期刊：
影响因子：
82.9
通讯作者：
Massague, Joan
中科院分区：
文献类型：
--
作者：
Laughney, Ashley M.;Hu, Jing;Massague, Joan
正常组织再生的发育过程与癌症有关，但它们在肿瘤进展过程中以及在免疫监视的选择性压力下的发挥程度仍然未知。在这里，我们表明，人类原发性肺腺癌的特征是再生细胞类型的出现，通常在对肺损伤的反应中出现，以及指定大多数肺泡和支气管上皮谱系的转录因子之间的惊人不忠实。相比之下，转移瘤富含关键内胚层和肺特异性转录因子 SOX2 和 SOX9，并概括了跨越干细胞样到再生肺上皮祖细胞状态的更原始转录程序。这种发育连续体反映了小鼠模型中从转移休眠自发爆发的进展阶段，并表现出 SOX9 依赖性的对自然杀伤细胞的抵抗力。自然杀伤细胞耗竭引发的宏转移中发育阶段特异性约束的丧失表明转移过程中发育可塑性和免疫介导的修剪之间存在动态相互作用。肺癌进展的单细胞分析揭示了转移爆发期间癌细胞和免疫介导的修剪共同选择的发育和再生程序
Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.Single-cell analysis of lung cancer progression uncovers developmental and regenerative programs co-opted by cancer cells and immune-mediated pruning during metastatic outbreak