Single-cell and bulk RNA sequencing reveal ligands and receptors associated with worse overall survival in serous ovarian cancer

Abstract

Background Serous ovarian carcinoma is the most frequent histological subgroup of ovarian cancer and the leading cause of death among gynecologic tumors. The tumor microenvironment and cancer-associated fibroblasts (CAFs) have a critical role in the origin and progression of cancer. We comprehensively characterized the crosstalk between CAFs and ovarian cancer cells from malignant fluids to identify specific ligands and receptors mediating intercellular communications and disrupted pathways related to prognosis and therapy response. Methods Malignant fluids of serous ovarian cancer, including tumor-derived organoids, CAFs-enriched (eCAFs), and malignant effusion cells (no cultured) paired with normal ovarian tissues, were explored by RNA-sequencing. These data were integrated with single-cell RNA-sequencing data of ascites from ovarian cancer patients. The most relevant ligand and receptor interactions were used to identify differentially expressed genes with prognostic values in ovarian cancer. Results CAF ligands and epithelial cancer cell receptors were enriched for PI3K-AKT, focal adhesion, and epithelial-mesenchymal transition signaling pathways. Collagens, MIF, MDK, APP, and laminin were detected as the most significant signaling, and the top ligand-receptor interactions THBS2/THBS3 (CAFs)—CD47 (cancer cells), MDK (CAFs)—NCL/SDC2/SDC4 (cancer cells) as potential therapeutic targets. Interestingly, 34 genes encoding receptors and ligands of the PI3K pathway were associated with the outcome, response to treatment, and overall survival in ovarian cancer. Up-regulated genes from this list consistently predicted a worse overall survival (hazard ratio > 1.0 and log-rank P < 0.05) in two independent validation cohorts. Conclusions This study describes critical signaling pathways, ligands, and receptors involved in the communication between CAFs and cancer cells that have prognostic and therapeutic significance in ovarian cancer.

ptx3a+ fibroblast/epicardial cells provide a transient macrophage niche to promote heart regeneration

“…We identified 5 primary signaling pathways in both zebrafish ( Figure 5A ) and neonatal mice Fb/Epi cells ( Figure 5B ), among which 4 signaling molecules are associated with reparative macrophages, including Csf1 , 57 , 58 Cxcl12 , 59 Angptl4 , 60 and Mdk 61 pathways. In macrophages, we identified expression of Csf1r , 57 Sdc4 , 62 , 63 and Cxcr4 64 as the primary receptors of these signals. We noticed that the CSF signaling pathway was highly specific in outgoing signals from Fb/Epi cells to macrophages compared to other signaling pathways from mesodermal/endothelial/endocardial (Mes/EC/Endo) cells ( Figures 5C and 5D ).…”

YTHDF2 favors protumoral macrophage polarization and implies poor survival outcomes in triple negative breast cancer

“…Compared with YTHDF2 -low macrophages, YTHDF2 -high macrophages exhibited pro-tumoral characteristics with multiple malignancy-promoting signals involved, such as RARRES2, MDK-SDC4/SDC2, CX3CL1-CX3CR1, COL4A5, COL4A2, COL4A1, C3AR1, TNFRSF1A, LILRB1, CCL5, ITGAV, SDC4, CD36, CD47, NRP1, and NRP2 ( Figures 5 A–5C). 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 In particular, some prominent pro-tumoral molecules 31 including MSR1, CCL18, STAB1, CD163L1, MERTK, AXL, GPNMB, and CHI3L1 were highly expressed by YTHDF2 -high macrophages while some prominent anti-tumoral ones 31 including IL1B, CCL2, CCL3, CCL4, TNF, CXCL2, and SOCS3 were highly expressed by YTHDF2 -low macrophages ( Figure 5 D). In summary, our observations demonstrate the pro-tumoral tendency of YTHDF2 -high macrophages.…”

Pan-cancer analysis for the prognostic and immunological role of CD47: interact with TNFRSF9 inducing CD8 + T cell exhaustion

“…Specifically, these cell types, including CAFs, Tregs, M2-TAMs, and MDSCs, have been recognized as biomarkers associated with T-cell exclusion within the tumor microenvironment (TME) [ 56 – 59 ].The interaction between CAFs and CD47 involves the receptor THBS2/THBS3 on CAFs interacting with CD47 expressed on cancer cells, promoting further cancer progression. Another receptor on the cell membrane of CAFs, MDK, interacts with NCL/SDC2/SDC on cancer cells, potentially serving as therapeutic targets [ 60 ]. Regarding the current understanding of the relationship between regulatory T cells (Tregs) and CD47, research has indicated that the ligand of CD47, SIRPγ, is expressed on T cells and varies with differentiation.…”