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

*Corresponding author for this work

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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.].

Original languageEnglish
Article number176
JournalCell Communication and Signaling
Volume20
Number of pages19
ISSN1478-811X
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • Cancer-associated fibroblasts
  • Cell–cell communication
  • Organoids
  • Serous ovarian cancer
  • Single-cell RNA-sequencing
  • Humans
  • Phosphatidylinositol 3-Kinases/metabolism
  • RNA/metabolism
  • Sequence Analysis, RNA
  • Fibroblasts/metabolism
  • Cell Line, Tumor
  • Female
  • Ligands
  • Tumor Microenvironment/genetics
  • Ovarian Neoplasms/pathology

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