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 2

RECK suppresses spontaneous Kras-driven PDAC formation.

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RECK suppresses spontaneous Kras-driven PDAC formation. (A) Schematic re...
(A) Schematic representation of the Cre-mediated recombination in pancreatic epithelial cells of KRC mice. Note that Ptf1a-Cre is expressed specifically in the progenitors of pancreatic ductal, exocrine, and endocrine cells (31). (B) Macroscopic views of the incised abdomen (scale bar: 10 mm), microscopic images of pancreatic sections after H&E staining, and immunofluorescence double staining for RECK (green) and CK19 (red) followed by nuclear counterstaining (Hoechst 33342; blue). Scale bar: 50 μm. Left column: Ptf1a-Cre; LSL-KrasG12D (KC) mice; right column: Ptf1a-Cre; LSL-KrasG12D; Reckfl/fl (KRC) mice. Both groups of mice were at 30 weeks of age. Green dotted lines outline the pancreas, and the yellow dotted line outlines tumor. (C) Frequency of PDAC formation in KC and KRC mice at indicated range of age. P = 0.0038 at 36–60 weeks of age, Fisher’s exact test. (D) Immunostaining for epithelial and mesenchymal markers in pancreatic tissue sections from KC (left) and KRC mice (right). E-cadherin, N-cadherin, or Zeb1 were detected followed by hematoxylin counterstaining. Scale bar: 50 μm. (E) Kaplan-Meier survival curves for KC and KRC mice. n = 70 (KC); n = 43 (KRC). P = 0.0007, log-rank test.