Department of Cell Biology, Duke University, Durham, NC 27710, USA; Duke Cancer Institute, Duke University, Durham, NC 27710, USA; Division of Pulmonary Critical care, Department of Medicine, Duke University School of Medicine, 307 Research Dr., Nanaline Duke Building, Room 308, Durham, NC 27710, USA; Regeneration Next, Duke University, Durham, NC 27710, USA.
Department of Genetics, Systems Biology Institute, Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT 06510, USA.
Dev Cell. 2018 Mar 26;44(6):679-693.e5. doi: 10.1016/j.devcel.2018.02.024.
We show that the loss or gain of transcription factor programs that govern embryonic cell-fate specification is associated with a form of tumor plasticity characterized by the acquisition of alternative cell fates normally characteristic of adjacent organs. In human non-small cell lung cancers, downregulation of the lung lineage-specifying TF NKX2-1 is associated with tumors bearing features of various gut tissues. Loss of Nkx2-1 from murine alveolar, but not airway, epithelium results in conversion of lung cells to gastric-like cells. Superimposing oncogenic Kras activation enables further plasticity in both alveolar and airway epithelium, producing tumors that adopt midgut and hindgut fates. Conversely, coupling Nkx2-1 loss with foregut lineage-specifying SOX2 overexpression drives the formation of squamous cancers with features of esophageal differentiation. These findings demonstrate that elements of pathologic tumor plasticity mirror the normal developmental history of organs in that cancer cells acquire cell fates associated with developmentally related neighboring organs.
我们表明，控制胚胎细胞命运特化的转录因子程序的丧失或获得与肿瘤可塑性的一种形式有关，这种可塑性的特征是获得通常与相邻器官相关的替代细胞命运。在人类非小细胞肺癌中，肺谱系特异性 TF NKX2-1 的下调与具有各种肠道组织特征的肿瘤相关。Nkx2-1 从鼠肺泡而非气道上皮细胞的缺失导致肺细胞转化为胃样细胞。致癌 Kras 的激活叠加进一步增加了肺泡和气道上皮细胞的可塑性，产生了具有中肠和后肠命运的肿瘤。相反，将 Nkx2-1 的缺失与前肠谱系特异性 SOX2 的过表达相结合，可驱动具有食管分化特征的鳞状细胞癌的形成。这些发现表明，病理性肿瘤可塑性的要素反映了器官的正常发育史，即癌细胞获得与发育相关的相邻器官相关的细胞命运。
