Theranostics 2020; 10(22):10274-10289. doi:10.7150/thno.47001 This issue Cite
Research Paper
1. Department of General Surgery, Shenzhen University General Hospital / Shenzhen University Clinical Medical Academy, Shenzhen, Guangdong 518055, China.
2. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
3. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 117593.
4. Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
5. Hepato-pancreato-biliary Surgery Department, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518055, China.
6. Department of Critical Care Medicine, National Cancer Center/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong 518116, China.
7. Cancer Center of Kyushu University Hospital, Fukuoka 812-8582, Japan.
8. NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117593.
9. National University Cancer Institute, National University Health System, Singapore 119074.
10. Carson International Cancer Research Centre, Shenzhen University School of Medicine, Shenzhen, Guangdong 518055, China.
*These authors contributed equally to this article.
Rationale: Pancreatic cancer is one of the most difficult cancers to manage and its poor prognosis stems from the lack of a reliable early disease biomarker coupled with its highly metastatic potential. Liver metastasis accounts for the high mortality rate in pancreatic cancer. Therefore, a better understanding of the mechanism(s) underlying the acquisition of the metastatic potential in pancreatic cancer is highly desirable.
Methods: Microarray analysis in wild-type and highly liver metastatic human pancreatic cancer cell lines was performed to identify gene expression signatures that underlie the metastatic process. We validated our findings in patient samples, nude mice, cell lines and database analysis.
Results: We identified a metastasis-related gene, laminin subunit alpha 4 (LAMA4), that was upregulated in highly liver metastatic human pancreatic cancer cell lines. Downregulation of LAMA4 reduced the liver metastatic ability of pancreatic cancer cells in vivo. Furthermore, LAMA4 expression was positively correlated with tumor severity and in silico analyses revealed that LAMA4 was associated with altered tumor microenvironment. In particular, our in vitro and in vivo results showed that LAMA4 expression was highly correlated with cancer-associated fibroblasts (CAFs) level which may contribute to pancreatic cancer metastasis. We further found that LAMA4 had a positive effect on the recruitment and activity of CAFs.
Conclusions: These data provide evidence for LAMA4 as a possible biomarker of disease progression and poor prognosis in pancreatic cancer. Our findings indicate that LAMA4 may contribute to pancreatic cancer metastasis via recruitment or activation of CAFs.
Keywords: LAMA4, metastasis, cancer-associated fibroblasts, tumor severity, pancreatic cancer