Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, Institut Necker Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Dev Cell. 2019 Oct 7;51(1):113-128.e9. doi: 10.1016/j.devcel.2019.07.022. Epub 2019 Aug 22.
Employing inducible genetically engineered and orthotopic mouse models, we demonstrate a key role for transcriptional regulator Yap in maintenance of Kras-mutant pancreatic tumors. Integrated transcriptional and metabolomics analysis reveals that Yap transcribes Myc and cooperates with Myc to maintain global transcription of metabolic genes. Yap loss triggers acute metabolic stress, which causes tumor regression while inducing epigenetic reprogramming and Sox2 upregulation in a subset of pancreatic neoplastic cells. Sox2 restores Myc expression and metabolic homeostasis in Yap-deficient neoplastic ductal cells, which gradually re-differentiate into acinar-like cells, partially restoring pancreatic parenchyma in vivo. Both the short-term and long-term effects of Yap loss in inducing cell death and re-differentiation, respectively, are blunted in advanced, poorly differentiated p53-mutant pancreatic tumors. Collectively, these findings reveal a highly dynamic and interdependent metabolic, transcriptional, and epigenetic regulatory network governed by Yap, Myc, Sox2, and p53 that dictates pancreatic tumor metabolism, growth, survival, and differentiation.
利用可诱导的基因工程和原位小鼠模型，我们证明了转录调节剂 Yap 在维持 Kras 突变的胰腺肿瘤中起着关键作用。综合转录组学和代谢组学分析表明， Yap 转录 Myc，并与 Myc 合作维持代谢基因的全局转录。 Yap 的缺失会引发急性代谢应激，导致肿瘤消退，同时在一部分胰腺肿瘤细胞中诱导表观遗传重编程和 Sox2 的上调。Sox2 在 Yap 缺陷的肿瘤导管细胞中恢复 Myc 的表达和代谢平衡，这些细胞逐渐重新分化为腺泡样细胞，在体内部分恢复胰腺实质。在诱导细胞死亡和重新分化方面，分别在晚期、分化不良的 p53 突变胰腺肿瘤中， Yap 缺失的短期和长期效应均减弱。总的来说，这些发现揭示了一个由 yap、Myc、Sox2 和 p53 控制的高度动态和相互依存的代谢、转录和表观遗传调控网络，该网络决定了胰腺肿瘤的代谢、生长、存活和分化。
