title: Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma.
abstract: 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.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Weiying
authors.initials: W
authors.lastname: Zhang
authors.forename: Nivedita
authors.initials: N
authors.lastname: Nandakumar
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Shi
authors.forename: Mark
authors.initials: M
authors.lastname: Manzano
authors.forename: Alias
authors.initials: A
authors.lastname: Smith
authors.forename: Garrett
authors.initials: G
authors.lastname: Graham
authors.forename: Swati
authors.initials: S
authors.lastname: Gupta
authors.forename: Eveline E
authors.initials: EE
authors.lastname: Vietsch
authors.forename: Sean Z
authors.initials: SZ
authors.lastname: Laughlin
authors.forename: Mandheer
authors.initials: M
authors.lastname: Wadhwa
authors.forename: Mahandranauth
authors.initials: M
authors.lastname: Chetram
authors.forename: Mrinmayi
authors.initials: M
authors.lastname: Joshi
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Kallakury
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Toretsky
authors.forename: Anton
authors.initials: A
authors.lastname: Wellstein
authors.forename: Chunling
authors.initials: C
authors.lastname: Yi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D018450:Disease Progression; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D051379:Mice; D009154:Mutation; D010183:Pancreatic Ducts / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human