Affiliation:
1. The Second Hospital of Dalian Medical University
Abstract
Abstract
Brain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many solid tumors, has been reported to be involved in the progression of multiple tumors. However, its potential involvement in BM of NSCLC and the underlying mechanism remain unknown. In this study, we found that MSLN expression was significantly elevated in both serum and tumor tissue samples from NSCLC patients with BM and correlated with a poor clinical prognosis. Our in vitro and ex vivo experiments demonstrated that MSLN significantly enhanced the brain metastatic abilities of NSCLC cells, especially blood–brain barrier (BBB) extravasation. Mechanistically, we found that MSLN facilitated the expression and activation of MET through the c-Jun N-terminal kinase (JNK) signaling pathway, which allowed tumor cells to disrupt tight junctions and the integrity of the BBB and thereby penetrate the barrier. Intriguingly, our in vivo experiments indicated that drugs targeting MSLN (anetumab) and MET (crizotinib) effectively blocked the development of BM and prolonged the survival of mice, with anetumab showing a superior therapeutic effect compared with crizotinib. In conclusion, our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.
Publisher
Research Square Platform LLC
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