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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 to 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 both primary tumor growth and establishment of metastases. By inducing SerRS overexpression after primary tumor implantation, we demonstrate the potential of SerRS as an anticancer therapeutic. Through tumor RNA-Seq, we identify 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 our knowledge, this is the first study to show a translation factor can act as both a tumor and metastasis suppressor.

ORGANISM(S): Mus musculus

PROVIDER: GSE264557 | GEO | 2025/02/19

REPOSITORIES: GEO

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Project description:Lymph-node (LN) metastases predict for high recurrence rates in breast cancer patients. Eradication of micro-metastatic tumor cells is the primary goal of adjuvant systemic treatment. Decisions regarding systemic treatment depend largely on primary tumor characteristics rather than on characteristics of their LN metastases. However, it remains unclear to what extent LN metastases, having already metastasized locally, resemble their primary breast tumors and as such will be eradicated by the systemic therapy chosen. In this study we investigated the genetic differences between primary breast cancers and their paired LN metastases using array comparative genomic hybridization analyses on a high resolution 720K Nimblegen platform. Thus far, no metastasis-specific genomic aberrations have been identified. We hypothesized that this is due to low-resolution platforms and lack of stratification on breast cancer subtypes (specifically, triple-negative (TN) versus luminal). Furthermore, we speculated that as TN tumours are known to be more genetically unstable, their LN metastases would show an increase in random copy number aberrations (CNAs). Therefore, we studied 10 primary TN breast tumour–LN pairs and 10 luminal pairs and found that all LN metastases clustered nearest to their matched tumour except for two. These two were explained by poor hybridization quality and, interestingly, the presence of two histological components in one tumour. We found no significantly altered CNAs between pairs in the whole group, nor when subdivided over subtypes; neither did we find a CNA increase in LN metastases compared to primary tumours within the TN subgroup, suggesting most CNAs are functional and not random. Our findings suggest a strong clonal relationship between primary breast tumours and its LN metastases and support the use of the primary tumor characteristics to guide adjuvant systemic chemotherapy in breast cancer patients, since primary tumors and their subsequent LN metastases seem remarkably similar, at least prior to treatment. The experiment contains 27 paired primary breast cancer samples with their lymph node metastases, analysed on a 135K whole genome CGH array

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

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