Oncotarget

Research Papers:

Metadherin promotes metastasis by supporting putative cancer stem cell properties and epithelial plasticity in pancreatic cancer

Kensuke Suzuki, Shigetsugu Takano _, Hideyuki Yoshitomi, Hitoe Nishino, Shingo Kagawa, Hiroaki Shimizu, Katsunori Furukawa, Masaru Miyazaki and Masayuki Ohtsuka

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2017; 8:66098-66111. https://doi.org/10.18632/oncotarget.19802

Metrics: PDF 1533 views  |   HTML 3095 views  |   ?  


Abstract

Kensuke Suzuki1, Shigetsugu Takano1, Hideyuki Yoshitomi1, Hitoe Nishino1, Shingo Kagawa1, Hiroaki Shimizu1, Katsunori Furukawa1, Masaru Miyazaki1 and Masayuki Ohtsuka1

1Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

Correspondence to:

Shigetsugu Takano, email: [email protected]

Keywords: metadherin, pancreatic cancer, cancer stem cell, epithelial plasticity, MET

Received: February 21, 2017     Accepted: July 12, 2017     Published: August 02, 2017

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 19802