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 2

Pancreatic PBRM1 deletion accelerates the formation of precancerous lesions and leads to poorly differentiated pancreatic ductal adenocarcinoma with a poor prognosis.

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Pancreatic PBRM1 deletion accelerates the formation of precancerous lesi...
(A) The genetic strategy employed to activate oncogenic Kras and delete Pbrm1, specifically in the pancreas, obtained from the embryonic stage. (B) Representative hematoxylin and eosin (H&E), Alcian blue, and PBRM1 staining in Ptf1aCre; LSL-KrasG12D(KC), Ptf1aCre; LSL-KrasG12D; Pbrm1f/wt (KCPb+/–), and Ptf1aCre; LSL-KrasG12D; Pbrm1f/f (KCPb–/–) mice at 20 weeks of age. Scale bar: 200 μm (H&E and alcian blue); 50 μm (Pbrm1). Data are representative of 3 independent experiments. (C) Quantification of Alcian blue–positive late acinar-to-ductal metaplasia and PanINs determination by combining 3 independent sections from KC (n = 3), KCPb+/– (n = 3), and KCPb–/– (n = 3) mice at 8 weeks of age. *P < 0.05, 1-way ANOVA, followed by Tukey’s multiple comparison test. Data are shown as mean ± SE. (D) Quantification of Alcian blue–positive late acinar-to-ductal metaplasia and PanINs determination by combining 3 independent sections from KC (n = 4), KCPb+/– (n = 3), and KCPb–/– (n = 3) mice at 20 weeks of age. *P < 0.05, 1-way ANOVA, followed by Tukey’s multiple comparison test. Data are shown as mean ± SE. (E) Representative H&E, CK19, and PBRM1 staining in PDACs from KC, KCPb+/–, and KCPb–/– mice. Scale bar: 50 μm. Data are representative of 3 independent experiments. (F) Kaplan-Meier plots showing the overall survival in the cohorts of KC (n = 86) and KCPb–/– (n = 54) mice. The log-rank (Mantel-Cox) test was used to assess statistical significance. (G) Rate of PDAC incidence in KC (n = 25), KCPb+/– (n = 14), and KCPb–/– (n = 12) mice aged 20–30 weeks. *P < 0.05, Fisher’s exact test.