Polybromo 1/vimentin axis dictates tumor grade, epithelial-mesenchymal transition, and metastasis in pancreatic cancer
Munenori Kawai, … , Etsuro Hatano, Hiroshi Seno
Munenori Kawai, … , Etsuro Hatano, Hiroshi Seno
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e177533. https://doi.org/10.1172/JCI177533.
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Research Article Gastroenterology Oncology

Polybromo 1/vimentin axis dictates tumor grade, epithelial-mesenchymal transition, and metastasis in pancreatic cancer

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.

Authors

Munenori Kawai, Akihisa Fukuda, Munehiro Ikeda, Kei Iimori, Kenta Mizukoshi, Kosuke Iwane, Go Yamakawa, Mayuki Omatsu, Mio Namikawa, Makoto Sono, Tomonori Masuda, Yuichi Fukunaga, Munemasa Nagao, Osamu Araki, Takaaki Yoshikawa, Satoshi Ogawa, Yukiko Hiramatsu, Motoyuki Tsuda, Takahisa Maruno, Yuki Nakanishi, Dieter Saur, Tatsuaki Tsuruyama, Toshihiko Masui, Etsuro Hatano, Hiroshi Seno

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Figure 3

Pancreatic PBRM1 loss synergizes with oncogenic KRAS and heterozygous Trp53 deletion to yield poorly differentiated PDAC and induce liver metastasis with a poor prognosis.

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Pancreatic PBRM1 loss synergizes with oncogenic KRAS and heterozygous Tr...
(A) Genetic strategy used to activate oncogenic Kras and delete Pbrm1 and Trp53 specifically in the pancreas from the embryonic stage. (B) Representative H&E staining in PDAC from Ptf1aCre; LSL-KrasG12D; Trp53f/wt (KPC) (n = 16), Ptf1aCre; LSL-KrasG12D; Trp53f/wt; Pbrm1f/wt (KPCPb+/–) (n = 18) and Ptf1aCre; LSL-KrasG12D; Trp53f/wt; Pbrm1f/f (KPCPb–/–) (n = 20) mice at the primary site. Scale bar: 50 μm. (C) Rate of tumor grade 3 or 4 of PDACs in KPC (n = 16), KPCPb+/– (n = 19), and KPCPb–/– (n = 20) mice. (D) Representative H&E staining in the livers of KPC (n = 16) mice and metastatic PDAC in the livers of KPCPb+/– (n = 7) and KPCPb–/– (n = 11) mice. Scale bar: 50 μm. (E) Quantification of liver metastasis incidence in KPC (n = 16), KPCPb+/– (n = 15), and KPCPb–/– (n = 18) mice during moribund state. (F) Kaplan-Meier plots showing overall survival of KPC (n = 37) and KPCPb–/– (n = 52) mice. (G) Representative H&E staining in PDAC allografted subcutaneously or orthotopically with PDAC cells from KPC (n = 3) and KPCPb–/– (n = 3) mice. Scale bar: 50 μm. (H) Representative H&E and CK19 staining of liver metastases after injection of PDAC cells into the spleen of KPC (n = 3) and KPCPb–/– (n = 3) mice. Metastatic lesions were circled by blue lines in H&E staining. Scale bar: 500 μm. (I) Rate of CK19-positive areas determined by combining 3 independent sections of liver metastases after injection of PDAC cells into the spleen of KPC (n = 3) and KPCPb–/– (n = 3) mice. (J) Representative image of the scratch assay with PDAC cells from KPC (n = 3) and KPCPb–/– (n = 3) mice. (K) Quantification of the scratch assay using PDAC cells from KPC (n = 3) and KPCPb–/– (n = 3) mice. (L) Representative coimmunostaining of vimentin, CK19, and Hoechst in primary and metastatic lesions in KPCPb–/– mice (n = 3). Scale bar: 50 μm. (M) Quantification of the rate of the vimentin-positive cancer cells in primary and metastatic lesions in KPCPb–/– mice (n = 3). *P < 0.05. C, E, Fisher’s exact test. F, Log-rank (Mantel-Cox) test. I, K Student t test. M, paired t test. Data shown as mean ± SE.