Integrated Multi-Omics and Spatial Transcriptomics Reveal GUK1 as a Prognostic Biomarker Regulated by the TP53-HSF1...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Guanylate kinase 1 (GUK1) is vital for nucleotide metabolism but its role in breast cancer (BC) progression is unclear.
• Investigating GUK1 offers potential for novel prognostic markers and therapeutic targets in BC.

Purpose of the Study:

• To evaluate Guanylate kinase 1 (GUK1) as a prognostic biomarker in breast cancer.
• To explore GUK1 as a potential therapeutic target for invasive breast cancer.

Main Methods:

• Multi-omics data integration (TCGA, spatial transcriptomics, single-cell profiling).
• Machine learning (LASSO regression) for biomarker identification.
• Experimental validation: knockdown models, molecular docking, Surface Plasmon Resonance (SPR).

Main Results:

• GUK1 identified as a key metabolic driver, with high expression linked to poor survival, especially in HER2-positive and triple-negative BC.
• GUK1 spatial distribution correlates with tumor expansion and disease stage, associated with an immunosuppressive T-cell microenvironment.
• TP53 mutations drive GUK1 upregulation via HSF1, impacting cell migration and PI3K/mTOR signaling; high GUK1 predicts resistance to CDK4/6 inhibitors but sensitivity to Apitolisib.

Conclusions:

• GUK1 is a robust prognostic biomarker in invasive breast cancer, regulated by the TP53-HSF1 axis.
• GUK1's spatial characteristics and immune-modulating role highlight its potential in precision oncology.
• GUK1 targeting shows promise for enhancing sensitivity to PI3K/mTOR inhibitors in specific breast cancer subtypes.