Polybromo 1/vimentin axis dictates tumor grade, epithelial-mesenchymal transition, and metastasis in pancreatic cancer
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
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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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 4

Pancreatic PBRM1 loss synergizes with oncogenic KRAS and homozygous Trp53 deletion to accelerate the development of poorly differentiated PDAC and to facilitate the EMT of PDAC cells, resulting in a poor prognosis.

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Pancreatic PBRM1 loss synergizes with oncogenic KRAS and homozygous Trp5...
(A) Representative H&E staining of the pancreas from Ptf1aCre; LSL-KrasG12D; Trp53f/f (KP–/–C), Ptf1aCre; LSL-KrasG12D; Trp53f/f; Pbrm1f/wt (KP–/–CPb+/–), and Ptf1aCre; LSL-KrasG12D; Trp53f/f; Pbrm1f/f (KP–/–CPb–/–) mice at 3 weeks of age and 6-to-9 weeks of age in the moribund state. Scale bar: 50 μm. Data are representative of 3 independent experiments. (B) Rate of tumor grade 3 or 4 of PDACs in KP–/–C (n = 10), KP–/–CPb+/– (n = 14), and KP–/–CPb–/– (n = 23) mice. *P < 0.05, Fisher’s exact test. (C) Kaplan-Meier plots showing overall survival of KP–/–C (n = 31) and KP–/–CPb–/– (n = 51) mice. The log-rank (Mantel-Cox) test has been used to assess the statistical significance. (D) Representative coimmunostaining of vimentin and tdTomato in PDAC from Ptf1aCre; LSL-KrasG12D Trp53f/f; LSL-Rosatd–tomato (KP–/–CTomato) (n = 3) and Ptf1aCre; LSL-KrasG12D; Trp53f/f; Pbrm1f/f; LSL-Rosatd–tomato (KP–/–CPb–/–Tomato) (n = 3) mice. Scale bar: 50 μm. (E) Kaplan-Meier plots showing overall survival of KP–/–C mice treated with gemcitabine (n = 4) and KP–/–C mice without treatment with gemcitabine (n = 31). The log-rank (Mantel-Cox) test has been used to assess the statistical significance. (F) Kaplan-Meier plots showing overall survival of KP–/–CPb–/– mice treated with gemcitabine (n = 6) and KP–/–CPb–/– mice without treatment with gemcitabine (n = 51). The log-rank (Mantel-Cox) test has been used to assess the statistical significance. (G) Representative coimmunostaining of CK19 and ΔNp63 in PDAC from KP–/–C (n = 3) and KP–/–CPb–/– (n = 3) mice. Scale bar: 50 μm. (H) Quantification of the rate of the ΔNp63-positive cancer cells in PDAC from KP–/–C (n = 3) and KP–/–CPb–/– (n = 3) mice. *P < 0.05, Student t test. Data shown as mean ± SE.