NVTG-02 CIRCULAR RNAS AS NOVEL TARGETS IN BREAST-TO-BRAIN CANCER METASTASIS

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Abstract Breast-to-brain metastatic (BTB met) cancer constitutes a great challenge for modern medicine and science, and thus, a quest for the discovery of novel therapeutic targets is underway. As the research on protein-coding genes has brought only incremental progress in discovering such targets, much attention is currently devoted to understanding the role of non-coding RNAs, including a relatively recently discovered group of circular RNAs. These non-coding RNAs, which arise from linear RNA transcripts, possess a covalently closed structure that renders them resistant to RNA turnover and a specific circularization site sequence that allows their precise suppression while keeping the linear parental transcript intact. These features thus make them promising candidates for biomarkers and therapeutic targets. This project aimed to map the circular RNA landscape in a comprehensive model of BTB met cancer cells, primary breast carcinoma, primary brain tumor cells, and relevant non-malignant breast and brain cell controls. Despite different tissue-of-origin, the analysis of global circRNAomes showed striking similarities between BTB mets and glioblastoma stem-like cells (GSCs) and allowed the selection of reliable candidates for mechanistic studies. Interestingly, the circRNAome of BTB mets clustered particularly closely with mesenchymal GSC, the most aggressive and therapy-resistant subtype of GSCs. Efficient knockdown of candidate circular RNAs in BTB met cells by antisense oligonucleotides resulted in molecular and phenotypic alterations such as diminished viability and clonality, arrested cell cycle concurrent with increased expression of cyclin-dependent kinase inhibitors, and changed expression of epithelial-mesenchymal transition markers. These results thus demonstrated the role of circular RNAs in shaping the oncogenic traits of BTB met cells. Further research focuses on circular RNA-dependent chemotherapy resistance, stemness/differentiation balance, and relevant models of metastatic progression (primary site/pleural effusion/brain). Therefore, circular RNAs can serve as valuable biomarkers and promising novel mechanistic candidates whose modulation may become a paradigm-shifting therapeutic approach.

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