Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a high metastatic potential. However, the mechanism of metastatic colonization in PDAC remains poorly understood. Metadherin (MTDH) has emerged in recent years as a crucial mediator of metastasis in several cancer types, although the biological role of MTDH in PDAC has not been investigated. Here, we demonstrated the functional roles of MTDH in PDAC progression, especially focusing on the metastatic cascade. In vitro studies showed that MTDH provides cancer stem cell (CSC) properties in metastatic PDAC cells and contributes to anoikis resistance with epithelial characteristics in PDAC cells. We also performed in vivo studies using both orthotopic transplantation and intra-portal vein injection as experimental models of liver metastasis to examine the function of MTDH at the metastatic site. MTDH knockdown dramatically reduced the incidence of liver metastases along with epithelial features in both experimental mouse models. Collectively, MTDH facilitates metastatic colonization with putative CSC and epithelial properties in PDAC cells. PDAC cells were transiently treated with TGF-β1 to investigate the roles of MTDH on epithelial plasticity. Intriguingly, MTDH expression was negatively correlated with Twist1 expression during the Mesenchymal-Epithelial transition (MET) induction in metastatic PDAC cells. These results suggest that MTDH may contribute to MET induction via downregulation of Twsit1. Lastly, immunohistochemistry indicated that MTDH overexpression is closely associated with hematogenous metastasis and predicts poor prognosis in patients with PDAC. This is the first demonstration of MTDH function in PDAC metastatic colonization. Our data suggest that MTDH targeting therapy could be applied to control PDAC metastasis.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is the fourth mostfrequent tumor-related cause of death in the Western world [1]
We focused on the functional contribution of MTDH to metastasis and undergoing epithelial plasticity, involving putative cancer stem cell (CSC) functions in PDAC progression
We investigated the level of MTDH mRNA and protein expression in PDAC cell lines
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is the fourth mostfrequent tumor-related cause of death in the Western world [1]. 50% of patients with PDAC are diagnosed with unresectable disease with distant metastasis and about 70% of the patients who undergo radical surgical resection develop metastatic recurrence [3]. These data suggest the existence of distant micrometastasis even at early stage of carcinogenesis in PDAC. Especially in PDAC, it is of great clinical value to elucidate the mechanism underlying the outgrowth of disseminated cancer cells into macroscopic metastases
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