title: Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation.
abstract: Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-KrasG12D;Fbxw7fl/fl(KFCfl/fl) compound mice. We found that KFCfl/flmice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFCfl/flmice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFCfl/fland FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of KrasG12D-induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap.
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Parsels
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Lohse
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Pasca di Magliano
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: mmccrack@med.umich.edu.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Morgan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D043171:Chromosomal Instability; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D017353:Gene Deletion; D011905:Genes, ras; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D044767:Ubiquitin-Protein Ligases