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

Dormancy is an important factor influencing colorectal cancer (CRC) metastasis through diverse metabolic pathways and cell types. To elucidate its molecular mechanisms, bulk transcriptomic pathway scoring was integrated with single-cell RNA sequencing of epithelial, cancer stem, and immune cells to identify CRC dormancy-associated genes (CDAGs). Twenty-three CDAGs were identified. These genes were found to play a regulatory role in dormancy by participating in metabolic processes affecting energy supply or substance synthesis. In two independent CRC cohorts (GSE41258, GSE41568), machine learning models using these genes distinguished metastatic samples with area under the curve (AUC) of 0.79-0.87. High CDAG expression was associated with better recurrence-free survival in GSE41258 (p = 0.005), which remained significant after adjusting for age, sex, and adjuvant chemotherapy (p = 0.037). The prognostic value was validated in The Cancer Genome Atlas (TCGA) Colon and Rectal Cancer for progression-free survival (p = 0.004). Moreover, 20 CRC dormancy-associated drugs were identified, 12 of which were reported to be associated with CRC, two with experimental evidence of inhibiting CRC metastasis or recurrence. This study provided metabolic-oriented genes for characterizing CRC dormancy, which could distinguish metastatic samples and had independent prognostic value, and offered a foundation for further development of targeted therapeutic strategies.