Departments of Pediatrics, Stanford University, Stanford, CA, USA.
Departments of Genetics, Stanford University, Stanford, CA, USA.
Nat Commun. 2022 May 16;13(1):2690. doi: 10.1038/s41467-022-30416-2.
The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using intratumoral heterogeneity in small-cell lung cancer as a tractable model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
Notch 通路是一条保守的细胞间通讯通路，它控制着细胞命运的决定。在这里，我们试图确定 Notch 通路的激活如何抑制肺中的神经内分泌细胞命运，这是 Notch 信号转导协调的细胞命运决定的典型过程，但在分子水平上仍知之甚少。我们使用小细胞肺癌中的肿瘤内异质性作为一种易于处理的模型系统，揭示了转录调节剂 REST 和 YAP 作为促进神经内分泌到非神经内分泌转化的作用。我们进一步确定了在这个过程中 Notch 下游抑制 REST 特异性神经内分泌基因程序的作用。重要的是，我们验证了 REST 和 YAP 在肺发育和组织修复过程中的神经内分泌到非神经内分泌细胞命运转换中的重要性。总的来说，这些实验确定了 REST 和 YAP 在 Notch 驱动的抑制胚胎肺、成体肺和肺癌中的神经内分泌细胞命运中的保守作用。
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