Ligand-receptor Interactions as a Prognostic Tool in Bladder Cancer - Expert Commentary

Cell-cell communication in the tumor microenvironment is known to drive oncogenesis and is mediated by ligand-receptor interactions. Wang et al., therefore, aimed to investigate a network of ligand-receptor pairs to identify whether different associations could predict the patient’s prognosis or response to treatment.

To do so, researchers extracted clinical and gene expression data for 406 bladder cancer patients from the Cancer Genome Atlas (TCGA). In addition, they used two other publicly available datasets as validation cohorts. Using a meta-analysis across all three cohorts, the authors identified 94 ligand-receptor pairs with prognostic significance. Of these, 76 were associated with a poor prognosis, and 18 were associated with a better prognosis. Functional annotation analysis revealed that many of these ligand-receptor pairs were enriched for oncogenic pathways like the PI3K-Akt, JAK-STAT, and MAPK pathways.

Based on the expression of the ligand-receptor pairs, the TCGA cohort was clustered into three subtypes with distinct prognosis. The use of the 94 ligand-receptor pairs for classification was subsequently validated in the two validation cohorts. In the TCGA cohort, cluster 1 (C1) was associated with the poorest prognosis and was associated with clinical stage, grade, old age, primary tumor stage, and lymph node status. Patients in cluster 3 (C3), associated with the best prognosis, exhibited a high Th1:Th2 ratio, low proliferation of immune cells, lowest intratumoral heterogeneity, and high Th17. Patients in this cluster also exhibited a higher frequency of mutations in genes such as KDM6A and FGFR3. Similarly, gene set enrichment analysis revealed 17 hallmarks that were more activated in C1 than C3, and these included immune-related genes, thereby implicating high immune infiltration in C1 patients. Cancer-related pathways related to epithelial-to-mesenchymal transition and K-Ras signaling were similarly enriched in the C1 cluster. These results were verified in the two validation cohorts. Finally, to validate the clinical significance of the ligand-receptor pairs, Wang et al. generated a ligand-receptor score and found that patients with a low score showed significant increases in survival. Furthermore, a lower score was associated with a better response to anti-PD-L1 treatment, while a higher score was associated with a better response to chemotherapy.

In conclusion, Wang et al. provide evidence for the prognostic and predictive value of the ligand-receptor expression in bladder cancer patients. These gene interaction signatures are potential biomarkers.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


  1. Wang C, Wan H, Zhang H, Yang B, Huang WK, Sun W. Characterization of Ligand-Receptor Pair in Bladder Cancer Develops a Validated Scoring Model for Prognosis and Treatment Response. Front Cell Dev Biol. 2022;10:915798. Published 2022 Jun 17. doi:10.3389/fcell.2022.915798

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