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.

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和免疫监视的选择性压力下的作用程度仍然未知。在这里，我们展示了人类原发性肺腺癌的特征是出现了再生细胞类型，通常在肺损伤的反应中可见，并且在指定大多数肺泡和支气管上皮谱系的转录因子之间存在显着的不忠。相比之下，转移灶富含关键内胚层和肺特异性转录因子SOX2和SOX9, 并概括了更原始的转录程序，跨越干细胞样到再生肺上皮祖细胞状态。这种发育连续体反映了小鼠模型中从转移休眠中自发爆发的进展阶段，并表现出对自然杀伤细胞的SOX9依赖性抗性。由自然杀伤细胞耗竭引发的大转移中发育阶段特异性约束的丧失表明在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。