A Yap-Myc-Sox2-p53 Regulatory Network Dictates Metabolic Homeostasis and Differentiation in Kras-Driven Pancreatic Ductal Adenocarcinomas
A Yap-Myc-Sox2-p53 Regulatory Network Dictates Metabolic Homeostasis and Differentiation in Kras-Driven Pancreatic Ductal Adenocarcinomas
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DOI：
10.1016/j.devcel.2019.07.022
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发表时间：
2019-10-07
影响因子：
11.8
通讯作者：
Yi, Chunling
中科院分区：
文献类型：
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作者：
Murakami, Shigekazu;Nemazanyy, Ivan;Yi, Chunling
采用诱导型基因工程和原位小鼠模型，我们证明了转录调节因子雅普在维持Kras突变胰腺肿瘤中的关键作用。综合转录组学和代谢组学分析表明，雅普转录Myc，并与Myc协同维持代谢基因的整体转录。雅普缺失引发急性代谢应激，这导致肿瘤消退，同时诱导胰腺肿瘤细胞亚群中的表观遗传重编程和Sox 2上调。Sox 2恢复Yap缺陷的肿瘤导管细胞中Myc的表达和代谢稳态，其逐渐再分化成腺泡样细胞，部分恢复体内胰腺实质。雅普缺失在诱导细胞死亡和再分化方面的短期和长期作用在晚期低分化p53突变胰腺肿瘤中分别减弱。总的来说，这些发现揭示了由雅普、Myc、Sox 2和p53控制的高度动态和相互依赖的代谢、转录和表观遗传调控网络，其决定胰腺肿瘤的代谢、生长、存活和分化。
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.