Seryl-tRNA synthetase inhibits Wnt signaling and breast cancer progression and metastasis

Abstract

Tumors require ample protein synthesis to grow, and aminoacyl-tRNA synthetases, as critical translation factors, are expected to support cancer progression. Unexpectedly, overexpression of seryl-tRNA synthetase (SerRS) suppresses primary tumor growth of breast cancer. However, the effects of SerRS on metastasis have not been studied. We observe a decrease in SerRS expression in breast cancer patient metastases compared with matched primary tumors, suggesting an inhibitory role of SerRS in metastasis. Through mouse metastasis models using breast cancer cell lines overexpressing SerRS, we show that SerRS impedes not only primary tumor growth but also establishment of metastases, and the effect of SerRS on metastasis can be independent of its impact on the primary tumor. SerRS also inhibits tumor growth with induced, post-tumor-onset overexpression, demonstrating its potential as an anticancer therapeutic. Tumor RNA-seq analysis identified Wnt signaling among the top SerRS-regulated pathways. Using cell-based studies, we confirm SerRS suppresses Wnt signaling and metastatic processes in breast cancer cells. To the best of our knowledge, this is the first study to show a component of the translation machinery can act as both a tumor and metastasis suppressor.