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- Title
Mutated EPHA2 is a target for combating lymphatic metastasis in intrahepatic cholangiocarcinoma.
- Authors
Sheng, Yuanyuan; Wei, Jinwang; Zhang, Yu; Gao, Xiaomei; Wang, Zheng; Yang, Jing; Yan, Shican; Zhu, Ying; Zhang, Ze; Xu, Da; Wang, Chaoqun; Zheng, Yan; Dong, Qiongzhu; Qin, Lunxiu
- Abstract
Exploring the genetic aberrations favoring metastasis is important for understanding and developing novel strategies to combat cancer metastasis. It remains lack of effective treatment for the dismal prognosis of intrahepatic cholangiocarcinoma (ICC). Here, we aimed to study genetic alternations during lymph node metastasis of ICC and investigate potential mechanisms and clinical strategy focused on mutations. We performed whole‐exome sequencing and transcriptome sequencing on samples from 30 ICC patients, including lymph node metastases from five of the patients. We identified the alterations of genetic pattern related to lymph node metastases of ICC. EPHA2, a member of the tyrosine kinase family, was found to be frequently mutated in ICC. Correlation analysis indicated that EPHA2 mutations were closely associated with lymph node metastasis of ICC. In vitro and in vivo experiments revealed that EPHA2 mutations could lead to ligand independent phosphorylation of Ser897, and promote lymphatic metastasis of ICC, in which NOTCH1 signaling pathway played an important role. In both in vitro assays and patient‐derived xenografts, an inhibitor of Ser897 phosphorylation effectively suppressed the metastasis of ICC with mutated EPHA2. Our findings demonstrated that EPHA2 mutants may be an attractive therapeutic target for lymphatic metastasis of ICC. What's new? High likelihood of metastasis is the major reason for dismal prognosis of intrahepatic cholangiocarcinoma (ICC) and a tailored treatment strategy for ICC, especially to combat the metastasis process, is still lacking. Here, using exome sequencing, the authors revealed much genomic heterogeneity between metastatic and non‐metastatic ICCs and between primary lesions and lymph node metastases. They also found that EPHA2 mutations, particularly D739N, could promote lymph node metastasis in an EphrinA1‐independent manner. Inhibiting EPHA2 with small‐molecule inhibitors may thus be a novel way to combat lymphatic metastasis of ICC, particularly for patients with EPHA2 mutations and high phosphorylation levels of Ser897.
- Publication
International Journal of Cancer, 2019, Vol 144, Issue 10, p2440
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.31979