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

• Published in: The Journal of clinical investigation Vol. 133; no. 18; pp. 1 - 14
• Main Authors: Masuda, Tomonori, Fukuda, Akihisa, Yamakawa, Go, Omatsu, Mayuki, Namikawa, Mio, Sono, Makoto, Fukunaga, Yuichi, Nagao, Munemasa, Araki, Osamu, Yoshikawa, Takaaki, Ogawa, Satoshi, Masuo, Kenji, Goto, Norihiro, Hiramatsu, Yukiko, Muta, Yu, Tsuda, Motoyuki, Maruno, Takahisa, Nakanishi, Yuki, Masui, Toshihiko, Hatano, Etsuro, Matsuzaki, Tomoko, Noda, Makoto, Seno, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.09.2023
• Subjects: Acute phase proteins; Adenocarcinoma; Age; Animals; Biomedical research; Cadherins - genetics; Carcinogenesis; Carcinoma, Pancreatic Ductal - genetics; Development and progression; E-cadherin; Epithelial-Mesenchymal Transition - genetics; Gastroenterology; Gelatinase A; Genetic aspects; Genotype & phenotype; GPI-Linked Proteins - genetics; Health aspects; Humans; Inflammation; Liver; Liver Neoplasms - genetics; Medical prognosis; Metastases; Metastasis; Mice; Morphology; Oncology; Pancreas; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; Phenotypes; Physiological aspects; Proteins; Transcription factors; Transplantation; Tumor suppressor genes; Tumors; Japan; Oncology; Mouse models; Tumor suppressors; Gastroenterology; Cancer
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI161847

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.