%0 Journal Article
%A Kawai, Munenori
%A Fukuda, Akihisa
%A Ikeda, Munehiro
%A Iimori, Kei
%A Mizukoshi, Kenta
%A Iwane, Kosuke
%A Yamakawa, Go
%A Omatsu, Mayuki
%A Namikawa, Mio
%A Sono, Makoto
%A Masuda, Tomonori
%A Fukunaga, Yuichi
%A Nagao, Munemasa
%A Araki, Osamu
%A Yoshikawa, Takaaki
%A Ogawa, Satoshi
%A Hiramatsu, Yukiko
%A Tsuda, Motoyuki
%A Maruno, Takahisa
%A Nakanishi, Yuki
%A Saur, Dieter
%A Tsuruyama, Tatsuaki
%A Masui, Toshihiko
%A Hatano, Etsuro
%A Seno, Hiroshi
%T Polybromo 1/vimentin axis dictates tumor grade, epithelial-mesenchymal transition, and metastasis in pancreatic cancer.
%J The journal of clinical investigation
%V 135
%N 11
%@ 0021-9738
%C Ann Arbor, Mich.
%I ASCJ
%M DKFZ-2025-01139
%P e177533
%D 2025
%X 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.
%K Epithelial-Mesenchymal Transition
%K Pancreatic Neoplasms: pathology
%K Pancreatic Neoplasms: metabolism
%K Pancreatic Neoplasms: genetics
%K Animals
%K Vimentin: genetics
%K Vimentin: metabolism
%K Mice
%K Humans
%K Carcinoma, Pancreatic Ductal: genetics
%K Carcinoma, Pancreatic Ductal: metabolism
%K Carcinoma, Pancreatic Ductal: pathology
%K Transcription Factors: genetics
%K Transcription Factors: metabolism
%K Neoplasm Metastasis
%K Nuclear Proteins: genetics
%K Nuclear Proteins: metabolism
%K Gene Expression Regulation, Neoplastic
%K DNA-Binding Proteins
%K Cell Line, Tumor
%K Tumor Suppressor Protein p53: genetics
%K Tumor Suppressor Protein p53: metabolism
%K Proto-Oncogene Proteins p21(ras): genetics
%K Proto-Oncogene Proteins p21(ras): metabolism
%K Mice, Knockout
%K Neoplasm Grading
%K Neoplasm Proteins: genetics
%K Neoplasm Proteins: metabolism
%K Cancer (Other)
%K Epigenetics (Other)
%K Gastroenterology (Other)
%K Mouse models (Other)
%K Oncology (Other)
%K Vimentin (NLM Chemicals)
%K Transcription Factors (NLM Chemicals)
%K Nuclear Proteins (NLM Chemicals)
%K Vim protein, mouse (NLM Chemicals)
%K DNA-Binding Proteins (NLM Chemicals)
%K Trp53 protein, mouse (NLM Chemicals)
%K Tumor Suppressor Protein p53 (NLM Chemicals)
%K VIM protein, human (NLM Chemicals)
%K Proto-Oncogene Proteins p21(ras) (NLM Chemicals)
%K Neoplasm Proteins (NLM Chemicals)
%K Hras protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40454484
%R 10.1172/JCI177533
%U https://inrepo02.dkfz.de/record/301755