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

Robson Francisco Carvalho*, Luisa Matos do Canto, Cecilie Abildgaard, Mads Malik Aagaard, Monica Søgaard Tronhjem, Marianne Waldstrøm, Lars Henrik Jensen, Karina Dahl Steffensen, Silvia Regina Rogatto

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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. [MediaObject not available: see fulltext.].

OriginalsprogEngelsk
Artikelnummer176
TidsskriftCell Communication and Signaling
Vol/bind20
Antal sider19
ISSN1478-811X
DOI
StatusUdgivet - dec. 2022

Bibliografisk note

Funding Information:
The results shown here are in part based upon data generated by the Genotype-Tissue Expression project (GTEx) ( https://gtexportal.org/ ) and by the TCGA Research Network ( http://cancergenome.nih.gov/ ). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

Funding Information:
This study was supported by grants from the Region of Southern Denmark Research Fund (J.nr.: 20/14277, Efond 519), Denmark. The study was developed in collaboration with the Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES), in the scope of the Program CAPES-PrInt (process number 88887.310463/2018–00).

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