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Single-Cell Transcriptomic Analysis to Build a Microenvironment-Aware Bladder Cancer Prognostic Model - Expert Commentary

As treatments for bladder cancer (BC) become more targeted and specific, understanding the molecular underpinnings and subtypes becomes increasingly important. Technological advancements such as single-cell RNA-sequencing (scRNA-seq) have facilitated this process, leading to a deeper understanding of the tumor microenvironment (TME) components and factors underlying treatment resistance. In a recent important study, Safder et al. utilized scRNA-seq data to identify BC markers associated with prognosis.

The dataset consisted of 20,091 normal and tumor cells from BC patients. There were 403 differentially expressed genes (DEGs) between the tumor microenvironment and tumor cells. The investigators identified 25 genes with the most significant impact on overall survival (OS) and subsequently used a multivariate Cox regression to highlight eight genes that were correlated with survival. These genes were used to construct a prognostic model that divided patients into low- or high-risk groups based on a median risk score. The model was validated in a separate dataset. Patients in the high-risk category exhibited lower OS rates (p < 0.0001). The AUC values reflecting the performance of the model on the separate dataset exceeded 0.65 and were considered robust. Univariate and multivariate Cox regression analyses revealed that the model’s risk score was an independent prognostic factor (HR, 2.97; 95% CI, 2.28 - 3.90; p < 0.001).

In terms of molecular signatures, the high-risk group exhibited enrichment in epithelial-mesenchymal transition (EMT), angiogenesis, and cellular signaling pathways. Furthermore, high-risk patients exhibited altered levels of tumor-associated immune cells in the TME, including B cells, CD4+ T cells, CD8+ T cells, M2 macrophages, Th2 cells, and regulatory T cells. The expression of a prognostic gene, CD74, was strongly correlated with infiltration levels of dendritic cells, M1 macrophages, B cells, and CD4+ T cells (p < 0.0001).

The identification of genes resolved at the single-cell resolution that are linked to survival outcomes in bladder cancer contributes to our understanding of the molecular mechanisms underpinning progression. Additional mechanistic studies of the role of the genes identified in this study can yield important insights into their role in cancer cell-microenvironment interactions and clinical outcomes.

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

References:

  1. Safder I, Valentine H, Uzzo N, et al. Identification and Validation of Prognostic Model for Tumor Microenvironment-Associated Genes in Bladder Cancer Based on Single-Cell RNA Sequencing Data Sets. JCO Precis Oncol. 2024;8:e2300661. doi:10.1200/PO.23.00661
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