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A Yap-Myc-Sox2-p53 Regulatory Network Dictates Metabolic Homeostasis and Differentiation in Kras-Driven Pancreatic Ductal Adenocarcinomas.

Developmental cell (2019-08-27)
Shigekazu Murakami, Ivan Nemazanyy, Shannon M White, Hengye Chen, Chan D K Nguyen, Garrett T Graham, Dieter Saur, Mario Pende, Chunling Yi
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
硫酸水素ナトリウム, technical grade
Sigma-Aldrich
イノシン, ≥99% (HPLC)
Sigma-Aldrich
AICAR, ≥98% (HPLC), powder
Sigma-Aldrich
Anti-Sox9 Antibody, Chemicon®, from rabbit
Sigma-Aldrich
抗α-アミラーゼ ウサギ宿主抗体, fractionated antiserum, lyophilized powder