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

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Ovarian cancer is a leading cause of cancer mortality with limited treatment options.
• Fragile X-related protein 1 (FXR1) is overexpressed in ovarian and other cancers, regulating oncogene translation.
• FXR1 represents a potential therapeutic target for ovarian cancer treatment.

Purpose of the Study:

• To investigate the therapeutic potential of FXR1 silencing in ovarian cancer.
• To evaluate the efficacy of locked nucleic acid-modified siRNA (siFXR1-LNA) targeting FXR1.
• To analyze the impact of FXR1 silencing on tumor microenvironment and immune cells.

Main Methods:

• RNA interference (RNAi) using siFXR1-LNA in ovarian cancer models.
• In vivo studies assessing tumor growth, ascites, and metastasis.
• Single-cell RNA sequencing (scRNA-seq) to analyze cellular composition of ascites.
• Assessment of immune cell populations within the tumor microenvironment.

Main Results:

• siFXR1-LNA demonstrated superior inhibition of tumor growth, ascites, and metastasis compared to native siRNA.
• LNA modification enhanced siRNA stability and tumor tissue uptake, leading to robust mRNA inhibition.
• FXR1 silencing suppressed tumor cell proliferation and reduced M2-like macrophages.
• FXR1 silencing increased cytotoxic T cells, NK cells, and dendritic cells with anti-tumor functions.

Conclusions:

• FXR1 is a critical regulator of oncogenic processes and a therapeutic liability in ovarian cancer.
• FXR1 silencing via siFXR1-LNA is an effective strategy for treating FXR1-expressing ovarian tumors.
• Targeting FXR1 modulates both tumor cells and the tumor immune microenvironment.