Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis
Tomonori Masuda, … , Makoto Noda, Hiroshi Seno
Tomonori Masuda, … , Makoto Noda, Hiroshi Seno
Published September 15, 2023
Citation Information: J Clin Invest. 2023;133(18):e161847. https://doi.org/10.1172/JCI161847.
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Research Article Gastroenterology Oncology

Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis

Abstract

RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast–like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC.

Authors

Tomonori Masuda, Akihisa Fukuda, Go Yamakawa, Mayuki Omatsu, Mio Namikawa, Makoto Sono, Yuichi Fukunaga, Munemasa Nagao, Osamu Araki, Takaaki Yoshikawa, Satoshi Ogawa, Kenji Masuo, Norihiro Goto, Yukiko Hiramatsu, Yu Muta, Motoyuki Tsuda, Takahisa Maruno, Yuki Nakanishi, Toshihiko Masui, Etsuro Hatano, Tomoko Matsuzaki, Makoto Noda, Hiroshi Seno

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Figure 3

RECK suppresses spontaneous liver metastasis of PDAC.

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RECK suppresses spontaneous liver metastasis of PDAC. (A) Morphology of ...
(A) Morphology of the excised liver (scale bar: 10 mm) and microscopic images of liver sections after H&E staining or immunofluorescence double staining for RECK (green) and CK 19 (red) followed by nuclear counterstaining (blue). Scale bar: 50 μm. Left column: KC mice; right column: KRC mice. Red dotted lines outline visible tumors. (B) Frequency of tumor metastasis to the liver in KC and KRC mice. P = 0.00925, Fisher’s exact test. (C) Immunostaining of epithelial and mesenchymal markers in liver tissues. Liver sections from KC (left) and KRC (right) mice were immunostained for E-cadherin and N-cadherin, followed by hematoxylin counterstaining. Scale bar: 50 μm. (D) Schematic representation of the Cre-mediated recombination resulting in Kras activation, p53 deletion, and Reck deletion in pancreatic epithelial cells in KPRC mice. Note that this diagram dose not explain the allelic composition. (E) Macroscopic views of the incised abdomen (scale bar: 10 mm) and microscopic images of pancreas sections stained with H&E or immunostained for E-cadherin, N-cadherin, or Zeb1, followed by hematoxylin counterstaining. Scale bar: 50 μm. Left column: KPC mice; right column: KPRC mice. Both groups of mice were at 18 weeks of age. Yellow dotted lines outline visible tumors. (F) Morphology of excised liver (scale bar: 10 mm) and images of liver sections after H&E staining (scale bar: 50 μm). Left column: KPC mice; right column: KPRC mice. Both groups of mice were at 18 weeks of age. (G) Frequency of liver metastasis of PDAC in KPC and KPRC mice. P = 0.009, Fisher’s exact test.