Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma
| Autor: | Mandheer Wadhwa, Yuhao Shi, Alias Smith, Swati Gupta, Mark Manzano, Nivedita Nandakumar, Anton Wellstein, Mahandranauth A. Chetram, Jeffrey A. Toretsky, Chunling Yi, Eveline E. Vietsch, Bhaskar Kallakury, Weiying Zhang, Garrett T. Graham, Sean Z. Laughlin, Fen Wang, Mrinmayi Joshi |
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| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Stromal cell endocrine system diseases Adenocarcinoma Biology medicine.disease_cause Biochemistry Article Mice medicine Animals Humans RNA Messenger neoplasms Molecular Biology Transcription factor Adaptor Proteins Signal Transducing Cell Proliferation Tumor microenvironment Hippo signaling pathway Pancreatic Ducts YAP-Signaling Proteins Cell Biology Genes p53 Phosphoproteins medicine.disease digestive system diseases Genes ras medicine.anatomical_structure Mutation Disease Progression Cancer research KRAS Pancreas Carcinoma Pancreatic Ductal Transcription Factors |
| Zdroj: | Science Signaling. 7 |
| ISSN: | 1937-9145 1945-0877 |
| DOI: | 10.1126/scisignal.2005049 |
| Popis: | Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates and frequently carries oncogenic KRAS mutation. However, KRAS has thus far not been a viable therapeutic target. We found that the abundance of YAP mRNA, which encodes Yes-associated protein (YAP), a protein regulated by the Hippo pathway during tissue development and homeostasis, was increased in human PDAC tissue compared with that in normal pancreatic epithelia. In genetically engineered Kras(G12D) and Kras(G12D):Trp53(R172H) mouse models, pancreas-specific deletion of Yap halted the progression of early neoplastic lesions to PDAC without affecting normal pancreatic development and endocrine function. Although Yap was dispensable for acinar to ductal metaplasia (ADM), an initial step in the progression to PDAC, Yap was critically required for the proliferation of mutant Kras or Kras:Trp53 neoplastic pancreatic ductal cells in culture and for their growth and progression to invasive PDAC in mice. Yap functioned as a critical transcriptional switch downstream of the oncogenic KRAS-mitogen-activated protein kinase (MAPK) pathway, promoting the expression of genes encoding secretory factors that cumulatively sustained neoplastic proliferation, a tumorigenic stromal response in the tumor microenvironment, and PDAC progression in Kras and Kras:Trp53 mutant pancreas tissue. Together, our findings identified Yap as a critical oncogenic KRAS effector and a promising therapeutic target for PDAC and possibly other types of KRAS-mutant cancers. |
| Databáze: | OpenAIRE |
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