Combined Analysis of Bulk and Single-Cell Transcriptomic Data Reveals Dormancy-Associated Genes in Colorectal Cancer

Area of Science:

• Molecular Oncology
• Cancer Metabolism
• Cancer Genomics

Background:

• Dormancy is a critical driver of colorectal cancer (CRC) metastasis, involving complex metabolic pathways and cellular interactions.
• Understanding the molecular underpinnings of CRC dormancy is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To identify colorectal cancer dormancy-associated genes (CDAGs) by integrating bulk transcriptomic pathway scoring with single-cell RNA sequencing.
• To investigate the role of CDAGs in CRC metastasis and their prognostic value.
• To identify potential therapeutic drugs associated with CRC dormancy.

Main Methods:

• Integrated bulk transcriptomic pathway scoring and single-cell RNA sequencing (scRNA-seq) of epithelial, cancer stem, and immune cells.
• Identified 23 CRC dormancy-associated genes (CDAGs) with regulatory roles in metabolic processes.
• Developed machine learning models using CDAGs to distinguish metastatic CRC samples in independent cohorts (GSE41258, GSE41568).
• Validated the prognostic significance of CDAGs in The Cancer Genome Atlas (TCGA) Colon and Rectal Cancer cohort.

Main Results:

• Twenty-three CDAGs were identified, primarily involved in metabolic processes crucial for energy supply and substance synthesis.
• Machine learning models incorporating CDAGs achieved high accuracy (AUC 0.79-0.87) in distinguishing metastatic CRC samples.
• High CDAG expression correlated with improved recurrence-free survival in one cohort and progression-free survival in TCGA, independent of clinical factors.
• Identified 20 CRC dormancy-associated drugs, including two with experimental evidence against CRC metastasis or recurrence.

Conclusions:

• Metabolic-oriented CDAGs effectively characterize CRC dormancy, distinguishing metastatic potential and offering independent prognostic value.
• These findings provide a foundation for developing novel therapeutic strategies targeting CRC dormancy and metastasis.
• The identified CDAGs and associated drugs represent promising avenues for future clinical translation in colorectal cancer treatment.