Loss of
TIPARP
‐Mediated
RNA
Regulatory Mechanisms Activates
TGF
‐β Signaling to Drive Fibroblast
Wenqi Fan, Chenchen Feng, Xiuying Chen, Haiyan Wang, Bin Li, Shien Zou, Ting Guo ABSTRACT
Background
Chemoresistance in ovarian cancer involves dynamic tumor microenvironment (TME) remodeling, yet the role of RNA regulatory mechanisms in stromal reprogramming remains unclear.
Methods
We integrated single‐cell RNA‐seq (GSE165897), spatial transcriptomics (GSE21956), and multi‐omics analyses from 11 ovarian cancer patients (resistant [Res] vs. sensitive [Sen] groups). FUSION pipeline identified RNA modification‐associated loci through regulome‐wide association studies (RWAS), while MAGMA linked GWAS variants to cell types. Functional assays included pseudotime trajectory (Monocle) and cell communication (CellChat).
Results
We identified 23 significant genes, including TIPARP, associated with RWAS loci. Fibroblasts in Res patients exhibited reduced TIPARP expression during differentiation, paralleling TGF‐β pathway activation. Spatial mapping revealed TGFB1+ endothelial cells co‐localized with TIPARP+ fibroblasts (Pearson's r = 0.71, p < 0.001). Mechanistically, TIPARP R‐loops overlapped TWAS regions (chr3:156672025–156711450), suggesting epigenetic regulation. Res‐fibroblasts showed activated TGF‐β signaling.
Conclusion
Reduced expression of TIPARP is associated with fibroblast chemoresistance via TGF‐β activation, highlighting a targetable RNA regulatory mechanism–stromal crosstalk axis.