Prognostic gene screening and experimental validation in renal clear cell carcinoma based on spatial transcriptomics...

Area of Science:

• Oncology
• Genomics
• Bioinformatics

Background:

• Clear cell renal cell carcinoma (ccRCC) presents significant challenges due to high recurrence and metastasis rates.
• There is an urgent need for novel prognostic biomarkers and therapeutic targets to enhance ccRCC patient stratification and treatment.
• Current therapeutic strategies require improvement to address the poor clinical outcomes associated with ccRCC.

Purpose of the Study:

• To identify robust prognostic gene signatures for ccRCC using integrated single-cell and spatial transcriptomics data.
• To develop and validate a predictive risk model for ccRCC patient survival.
• To uncover potential therapeutic targets, such as ATP1A1, and elucidate their functional roles in ccRCC progression.

Main Methods:

• Integration of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) data.
• Development of a prognostic risk model using seven identified genes (CYFIP2, MPPED2, HHLA2, ADAM8, ATP1A1, ARC, MXD3).
• Validation of the risk model and nomogram using The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets; functional analyses of candidate genes.

Main Results:

• A seven-gene prognostic model was established, effectively stratifying ccRCC patients into high- and low-risk groups with distinct survival outcomes.
• The model demonstrated strong predictive accuracy, validated across independent TCGA and ICGC cohorts, with a nomogram showing improved prediction when incorporating age.
• ATP1A1 was identified as a key target, highly expressed in endothelial cells, associated with M1 macrophages, and functionally involved in inhibiting angiogenesis and modulating M1 macrophage polarization.

Conclusions:

• The developed risk model and nomogram offer significant prognostic value for clinical risk stratification in ccRCC.
• ATP1A1 represents a promising therapeutic target with demonstrated roles in angiogenesis and immune modulation, supporting personalized ccRCC treatment.
• These findings underscore the clinical utility of identified gene signatures and pave the way for novel therapeutic strategies in ccRCC management.