DPPA3-HIF1a axis controls colorectal cancer chemoresistance by imposing a slow cell-cycle phenotype

Tumor relapse is linked to rapid chemoresistance and represents a bottleneck for cancer therapy success. Engagement of a reduced proliferation state is a non-mutational mechanism exploited by cancer cells to bypass therapy-induced cell death. Through combining functional pulse-chase experiments in engineered cells and transcriptomic analyses, we identify DPPA3 as a master regulator of slow-cycling and chemoresistant phenotype in colorectal cancer (CRC). We find a vicious DPPA3-HIF1a feedback loop that downregulates FOXM1 expression via DNA methylation, thereby delaying cell-cycle progression. Moreover, downregulation of HIF1a partially restores a chemosensitive proliferative phenotype in DPPA3-overexpressing cancer cells. In cohorts of CRC patient samples, DPPA3 overexpression acts as a predictive biomarker of chemotherapeutic resistance that subsequently requires reduction in its expression to allow metastatic outgrowth. Our work demonstrates that slow-cycling cancer cells exploit a DPPA3/HIF1a axis to support tumor persistence under therapeutic stress and provides insights on the molecular regulation of disease progression.

Automated summary

Tumor relapse and chemoresistance are major challenges in cancer therapy. This study reveals that DPPA3 plays a crucial role in promoting slow-cycling and chemoresistant phenotype in colorectal cancer. The study also uncovers a feedback loop between DPPA3 and HIF1a that regulates cell-cycle progression and highlights the potential of downregulating HIF1a to restore chemosensitivity. Furthermore, DPPA3 overexpression is identified as a biomarker for chemotherapeutic resistance in CRC patients.