The Journal of Clinical Investigation (Sep 2023)

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

  • 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

Journal volume & issue
Vol. 133, no. 18

Abstract

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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.

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