Integrative Multiomics and Single-Cell Analyses Identify FKBP10 as a Predictor of Radiotherapy Outcome in Colorectal...

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Radiotherapy resistance significantly limits treatment efficacy in colorectal cancer (CRC), with a low complete response rate of 15%-20%.
• There is a critical need for validated biomarkers to predict radiotherapy response and identify novel therapeutic targets in CRC.

Purpose of the Study:

• To identify novel biomarkers and therapeutic targets for overcoming radiotherapy resistance in colorectal cancer.
• To investigate the role of FKBP10 in mediating radioresistance within the tumor microenvironment.

Main Methods:

• Integrative multiomics analysis of 200 CRC patients, with independent validation in 58 patients.
• Single-cell RNA sequencing to determine cell-type-specific gene expression patterns.
• Functional validation in radiotherapy-resistant CRC cell lines using loss-of-function experiments.

Main Results:

• FKBP10 was identified as a statistically significant gene associated with radioresistance in both discovery and validation cohorts.
• Single-cell profiling revealed predominant FKBP10 expression in cancer-associated fibroblasts (CAFs), suggesting CAF-mediated stromal remodeling contributes to resistance.
• FKBP10 knockdown inhibited cancer cell proliferation, migration, and invasion, while enhancing radiosensitivity by increasing DNA damage.

Conclusions:

• FKBP10 is established as a reliable CAF-derived biomarker for radiotherapy resistance in CRC.
• FKBP10 represents a promising therapeutic target for developing novel combination strategies in precision cancer treatment.
• This study provides a foundation for FKBP10-targeted therapies to improve colorectal cancer treatment outcomes.