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@ARTICLE{Kawai:301755,
      author       = {M. Kawai and A. Fukuda and M. Ikeda and K. Iimori and K.
                      Mizukoshi and K. Iwane and G. Yamakawa and M. Omatsu and M.
                      Namikawa and M. Sono and T. Masuda and Y. Fukunaga and M.
                      Nagao and O. Araki and T. Yoshikawa and S. Ogawa and Y.
                      Hiramatsu and M. Tsuda and T. Maruno and Y. Nakanishi and D.
                      Saur$^*$ and T. Tsuruyama and T. Masui and E. Hatano and H.
                      Seno},
      title        = {{P}olybromo 1/vimentin axis dictates tumor grade,
                      epithelial-mesenchymal transition, and metastasis in
                      pancreatic cancer.},
      journal      = {The journal of clinical investigation},
      volume       = {135},
      number       = {11},
      issn         = {0021-9738},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DKFZ-2025-01139},
      pages        = {e177533},
      year         = {2025},
      abstract     = {Mutations in Polybromo 1 (PBRM1), a subunit of the
                      switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling
                      complex, are frequently observed in several cancers,
                      including pancreatic ductal adenocarcinoma (PDAC). In this
                      study, we demonstrated that pancreas-specific loss of Pbrm1
                      in mice harboring Kras mutations and Trp53 deletions
                      accelerated the development of poorly differentiated PDAC,
                      epithelial-mesenchymal transition (EMT), and metastasis,
                      resulting in worsened prognosis. Pbrm1 loss in preexisting
                      PDAC shifted the tumor grade from a well- to a poorly
                      differentiated state and elevated vimentin expression.
                      Pbrm1-null PDAC exhibited downregulation of apical junction
                      genes and upregulation of EMT pathway genes, including the
                      vimentin and squamous molecular subtype signature genes.
                      Mechanistically, PBRM1 bound to the vimentin gene promoter
                      and directly downregulated its expression. Furthermore,
                      suppression of vimentin in Pbrm1-null PDAC cells reversed
                      the dedifferentiation phenotype and reduced EMT and
                      metastasis. Consistently, reduced PBRM1 expression
                      correlated with high vimentin expression, poorly
                      differentiated histology, a high recurrence rate, and
                      reduced overall survival in human PDACs. Additionally, PDAC
                      with PBRM1 deletion was associated with the aggressive
                      squamous molecular subtype. Our data established PBRM1 as a
                      tumor suppressor that controls tumor grade and metastasis of
                      PDAC by regulating vimentin expression.},
      keywords     = {Epithelial-Mesenchymal Transition / Pancreatic Neoplasms:
                      pathology / Pancreatic Neoplasms: metabolism / Pancreatic
                      Neoplasms: genetics / Animals / Vimentin: genetics /
                      Vimentin: metabolism / Mice / Humans / Carcinoma, Pancreatic
                      Ductal: genetics / Carcinoma, Pancreatic Ductal: metabolism
                      / Carcinoma, Pancreatic Ductal: pathology / Transcription
                      Factors: genetics / Transcription Factors: metabolism /
                      Neoplasm Metastasis / Nuclear Proteins: genetics / Nuclear
                      Proteins: metabolism / Gene Expression Regulation,
                      Neoplastic / DNA-Binding Proteins / Cell Line, Tumor / Tumor
                      Suppressor Protein p53: genetics / Tumor Suppressor Protein
                      p53: metabolism / Proto-Oncogene Proteins p21(ras): genetics
                      / Proto-Oncogene Proteins p21(ras): metabolism / Mice,
                      Knockout / Neoplasm Grading / Neoplasm Proteins: genetics /
                      Neoplasm Proteins: metabolism / Cancer (Other) / Epigenetics
                      (Other) / Gastroenterology (Other) / Mouse models (Other) /
                      Oncology (Other) / Vimentin (NLM Chemicals) / Transcription
                      Factors (NLM Chemicals) / Nuclear Proteins (NLM Chemicals) /
                      Vim protein, mouse (NLM Chemicals) / DNA-Binding Proteins
                      (NLM Chemicals) / Trp53 protein, mouse (NLM Chemicals) /
                      Tumor Suppressor Protein p53 (NLM Chemicals) / VIM protein,
                      human (NLM Chemicals) / Proto-Oncogene Proteins p21(ras)
                      (NLM Chemicals) / Neoplasm Proteins (NLM Chemicals) / Hras
                      protein, mouse (NLM Chemicals)},
      cin          = {MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40454484},
      doi          = {10.1172/JCI177533},
      url          = {https://inrepo02.dkfz.de/record/301755},
}