TY  - JOUR
AU  - Kawai, Munenori
AU  - Fukuda, Akihisa
AU  - Ikeda, Munehiro
AU  - Iimori, Kei
AU  - Mizukoshi, Kenta
AU  - Iwane, Kosuke
AU  - Yamakawa, Go
AU  - Omatsu, Mayuki
AU  - Namikawa, Mio
AU  - Sono, Makoto
AU  - Masuda, Tomonori
AU  - Fukunaga, Yuichi
AU  - Nagao, Munemasa
AU  - Araki, Osamu
AU  - Yoshikawa, Takaaki
AU  - Ogawa, Satoshi
AU  - Hiramatsu, Yukiko
AU  - Tsuda, Motoyuki
AU  - Maruno, Takahisa
AU  - Nakanishi, Yuki
AU  - Saur, Dieter
AU  - Tsuruyama, Tatsuaki
AU  - Masui, Toshihiko
AU  - Hatano, Etsuro
AU  - Seno, Hiroshi
TI  - Polybromo 1/vimentin axis dictates tumor grade, epithelial-mesenchymal transition, and metastasis in pancreatic cancer.
JO  - The journal of clinical investigation
VL  - 135
IS  - 11
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DKFZ-2025-01139
SP  - e177533
PY  - 2025
AB  - 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.
KW  - Epithelial-Mesenchymal Transition
KW  - Pancreatic Neoplasms: pathology
KW  - Pancreatic Neoplasms: metabolism
KW  - Pancreatic Neoplasms: genetics
KW  - Animals
KW  - Vimentin: genetics
KW  - Vimentin: metabolism
KW  - Mice
KW  - Humans
KW  - Carcinoma, Pancreatic Ductal: genetics
KW  - Carcinoma, Pancreatic Ductal: metabolism
KW  - Carcinoma, Pancreatic Ductal: pathology
KW  - Transcription Factors: genetics
KW  - Transcription Factors: metabolism
KW  - Neoplasm Metastasis
KW  - Nuclear Proteins: genetics
KW  - Nuclear Proteins: metabolism
KW  - Gene Expression Regulation, Neoplastic
KW  - DNA-Binding Proteins
KW  - Cell Line, Tumor
KW  - Tumor Suppressor Protein p53: genetics
KW  - Tumor Suppressor Protein p53: metabolism
KW  - Proto-Oncogene Proteins p21(ras): genetics
KW  - Proto-Oncogene Proteins p21(ras): metabolism
KW  - Mice, Knockout
KW  - Neoplasm Grading
KW  - Neoplasm Proteins: genetics
KW  - Neoplasm Proteins: metabolism
KW  - Cancer (Other)
KW  - Epigenetics (Other)
KW  - Gastroenterology (Other)
KW  - Mouse models (Other)
KW  - Oncology (Other)
KW  - Vimentin (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - Nuclear Proteins (NLM Chemicals)
KW  - Vim protein, mouse (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - Trp53 protein, mouse (NLM Chemicals)
KW  - Tumor Suppressor Protein p53 (NLM Chemicals)
KW  - VIM protein, human (NLM Chemicals)
KW  - Proto-Oncogene Proteins p21(ras) (NLM Chemicals)
KW  - Neoplasm Proteins (NLM Chemicals)
KW  - Hras protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40454484
DO  - DOI:10.1172/JCI177533
UR  - https://inrepo02.dkfz.de/record/301755
ER  -