FGF7–FGFR2 Signaling Enhances Contractile Activation of CAFs in Ovarian Cancer: Integrative Single-Cell and Spatial Transcriptomics

Songwei Feng,1,* Zhaoyan Ding,2,* Yuru Wang,1 Zihan Zhu,2 Wen Zhong,2 Ke Zhang,3 Yueming Zhang,1 Li Chen,1 Yun Ma4 1Department of Obstetrics and Gynaecology, The Fourth Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Suzhou Medical College, Soochow University, Suzhou, People’s Republic of China; 3Department of Obstetrics and Gynaecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 4Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Chen, Email [email protected] Yun Ma, Email [email protected]: Background: Cancer-associated fibroblasts (CAFs) are a major stromal component of high-grade serous ovarian carcinoma (HGSOC), yet their functional programs and spatial organization remain incompletely defined and inconsistently reported across studies.Methods: We analyzed single-cell RNA-seq data from 7 treatment-naïve HGSOC tumors and integrated these findings with spatial transcriptomics from 4 HGSOC specimens. CAFs were re-clustered into functional programs, trajectories were inferred, and cell–cell communication was modeled. CAF states were mapped onto tissue sections using deconvolution and single-cell spatial mapping. Primary HGSOC CAFs and TGF-β–activated MRC5 fibroblasts (MRC5-CAFs) were used for collagen gel contraction and Western blot validation with perturbation of FGF7/FGFR2 signaling.Results: We identified three CAF programs: matrix-associated CAFs (mCAFs), metabolic-associated CAFs (meCAFs), and proliferative CAFs (pCAFs). Trajectory analyses suggested a continuum from pCAF to mCAF to meCAF. Communication analyses highlighted an FGF7–FGFR2 axis enriched in mCAFs. Spatial analyses indicated CAF-enriched regions were spatially segregated from immune-enriched regions. In vitro, recombinant FGF7 increased AKT phosphorylation and enhanced CAF contractile activation, whereas FGF7 neutralization or FGFR2 inhibition reduced AKT phosphorylation and contractility.Conclusion: Integrative single-cell, spatial, and functional analyses implicate an FGF7–FGFR2–PI3K/AKT axis in maintaining the contractile activation of CAFs in ovarian cancer, providing a rationale for targeting CAF signaling and ECM remodeling.Keywords: ovarian cancer, cancer-associated fibroblasts, FGF7, extracellular matrix, single-cell transcriptomics, spatial transcriptomics