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Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture
Published on: February 11, 2019
Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis
Tomonori Masuda1, Akihisa Fukuda1, Go Yamakawa1
1Department of Gastroenterology and Hepatology.
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.
Insights
Reck protein loss accelerates pancreatic cancer (PDAC) in mice, promoting metastasis and reducing survival. Restoring Reck inhibits cancer cell invasion and epithelial-mesenchymal transition, suggesting its tumor-suppressive role.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- RECK (Reversion-Inducing Cysteine-Rich Protein with Kazal Motifs) is frequently downregulated in human cancers.
- The precise role of RECK inactivation in carcinogenesis, particularly in pancreatic ductal adenocarcinoma (PDAC), remains largely undefined.
Purpose of the Study:
- To investigate the functional impact of RECK inactivation on PDAC development and progression.
- To elucidate the molecular mechanisms by which RECK influences PDAC phenotypes and metastasis.
Main Methods:
- Utilized a genetically engineered mouse model of PDAC with pancreatic Reck deletion.
- Employed lineage tracing, splenic transplantation assays, and molecular analyses (gene expression, protein levels).
- Correlated RECK expression with clinicopathological features in human PDAC samples.
Main Results:
- Pancreatic Reck deletion significantly accelerated spontaneous PDAC development, characterized by a mesenchymal phenotype, increased liver metastases, and reduced survival.
- Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, generating cancer-associated fibroblast-like cells.
- RECK reexpression suppressed MMP2/MMP3, increased E-cadherin, and decreased EMT-promoting transcription factors, reducing metastatic potential.
- Low RECK expression in human PDAC correlated with poor differentiation, metastasis, and worse prognosis.
Conclusions:
- RECK functions as a tumor suppressor in pancreatic cancer.
- RECK inactivation promotes PDAC progression and metastasis through EMT.
- RECK holds potential as a therapeutic target for human PDAC.
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