Single-cell transcriptomics reveals FXR1 as an actionable target for siRNA therapy in ovarian cancer

Abstract

Abstract Ovarian cancer is one of the leading causes of cancer-related mortality among women and remains exceptionally difficult to manage and treat effectively in the clinic. Fragile X-related protein 1 (FXR1) is highly amplified and overexpressed in ovarian and several other cancers. FXR1 is a key regulator of the translation of multiple oncogenes and therefore represents a vulnerable target for cancer therapy. RNA interference (RNAi) of FXR1 using a locked nucleic acid (LNA) form of siRNA (siFXR1-LNA) inhibits tumor growth, ascites formation, and metastasis of ovarian cancer more efficiently than the native form of FXR1 siRNA in vivo. LNA modification of siRNA improves resistance to RNase mediated degradation and enhances tumor tissue uptake of siRNA with robust inhibition of target mRNA in tumor tissues. Single-cell RNA sequencing (scRNA-seq) analysis of ascites composed of tumor, stromal, and immune cells analysis reveals that FXR1 silencing suppresses tumor cell proliferation and reduces tumor-promoting M2-like macrophages. FXR1 silencing also increases cytotoxic T cells, NK cells, and dendritic cells with anti-tumor characteristics in vivo. Collectively, our data establishes FXR1 as an important regulator of oncogenic processes in cancer tissues and serves as a therapeutic liability. Therefore, FXR1 silencing in tumor tissues provides an effective strategy to treat tumors expressing high levels of FXR1.