Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Med. 2020 Feb;26(2):259-269. doi: 10.1038/s41591-019-0750-6. Epub 2020 Feb 10.
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，但在肿瘤进展过程中以及在免疫监视的选择压力下，它们的实施程度尚不清楚。在这里，我们表明，人原发性肺腺癌的特征是出现再生细胞类型，这些细胞通常是对肺损伤的反应，并且转录因子的失配程度很大，这些转录因子指定大多数肺泡和支气管上皮谱系。相比之下，转移瘤富含关键的内胚层和肺特异性转录因子 SOX2 和 SOX9，并重现更原始的转录程序，跨越干细胞样到再生肺上皮祖细胞状态。这种发育连续性反映了自发性爆发从转移休眠的小鼠模型的进展阶段，并表现出 SOX9 依赖性对自然杀伤细胞的抵抗。自然杀伤细胞耗竭引发的巨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。
