Faculty Collaboration Database

Single-cell transcriptomics reveals FXR1 as an actionable target for siRNA therapy in ovarian cancer. Nat Commun 2026 Apr 03;17(1)

Date

04/04/2026

Pubmed ID

41932914

Pubmed Central ID

PMC13219712

DOI

10.1038/s41467-026-71468-y

Scopus ID

2-s2.0-105040524934 (requires institutional sign-in at Scopus site)   1 Citation

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.

Author List

George J, Ma X, Kadamberi IP, Nair A, Mittal S, Hashemi E, Kumar S, Singh M, Geethadevi A, Pradeep M, Nair A, Tsaih SW, Jorns JM, Malarkannan S, Dietlein F, Lin CW, Pradeep S, Chaluvally-Raghavan P

Authors

Pradeep Chaluvally-Raghavan PhD Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Julie M. Jorns MD Professor in the Pathology and Laboratory Medicine department at Medical College of Wisconsin
Chien-Wei Lin PhD Associate Professor in the Data Science Institute department at Medical College of Wisconsin
Subramaniam Malarkannan PhD Professor in the Medicine department at Medical College of Wisconsin
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Ascites
Cell Line, Tumor
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
Oligonucleotides
Ovarian Neoplasms
RNA Interference
RNA, Small Interfering
RNA-Binding Proteins
Single-Cell Analysis
Transcriptome