Single-cell transcriptional profiling of clear cell renal cell carcinoma reveals a tumor-associated endothelial tip cell phenotype

• Published in: Communications biology 2024-06, Vol.7 (1), p.780-15, Article 780
• Main Authors: Zvirblyte, Justina, Nainys, Juozas, Juzenas, Simonas, Goda, Karolis, Kubiliute, Raimonda, Dasevicius, Darius, Kincius, Marius, Ulys, Albertas, Jarmalaite, Sonata, Mazutis, Linas
• Format: Article
• Language: English
• Subjects: 38; 38/62; 38/71; 38/91; 45; 631/67/2329; 631/67/327; 631/67/69; Angiogenesis; Biomedical and Life Sciences; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Cell interactions; Clear cell-type renal cell carcinoma; Endothelial Cells - metabolism; Endothelial Cells - pathology; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genotype & phenotype; Humans; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Life Sciences; Male; Phenotype; Phenotypes; Single-Cell Analysis; Stromal cells; Transcriptome; Transcriptomes; Tumor microenvironment; Tumor Microenvironment - genetics; Tumors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06478-x

Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer, accounting for over 75% of cases. The asymptomatic nature of the disease contributes to late-stage diagnoses and poor survival. Highly vascularized and immune infiltrated microenvironment are prominent features of ccRCC, yet the interplay between vasculature and immune cells, disease progression and response to therapy remains poorly understood. Using droplet-based single-cell RNA sequencing we profile 50,236 transcriptomes from paired tumor and healthy adjacent kidney tissues. Our analysis reveals significant heterogeneity and inter-patient variability of the tumor microenvironment. Notably, we discover a previously uncharacterized vasculature subpopulation associated with epithelial-mesenchymal transition. The cell-cell communication analysis reveals multiple modes of immunosuppressive interactions within the tumor microenvironment, including clinically relevant interactions between tumor vasculature and stromal cells with immune cells. The upregulation of the genes involved in these interactions is associated with worse survival in the TCGA KIRC cohort. Our findings demonstrate the role of tumor vasculature and stromal cell populations in shaping the ccRCC microenvironment and uncover a subpopulation of cells within the tumor vasculature that is associated with an angiogenic phenotype. A comprehensive single-cell analysis of clear cell renal cell carcinoma reveals a previously uncharacterized tip-cell like endothelial phenotype and uncovers immunosuppressive clinically relevant targetable interactions in the tumor microenvironment.