Identication of ATF3 as a novel protective signature of quiescent colorectal tumor cells
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA-sequencing, we classified proliferating and quiescent cancer cell populations in human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs which could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of ATAC-Seq genomic tracing, STING analysis, and evaluation on TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at transcriptional and translational level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCC, and combining generic drugs targeting PCC with an option to target QCC by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.