Colon cancer cells survive and recover proliferation under prolonged glucose deprivation

Metabolic plasticity enables cancer cells to survive fluctuations in nutrient availability within the tumor microenvironment. Although most colorectal cancer (CRC) cells are highly dependent on glucose-driven glycolysis, we demonstrate that CRC cells can survive prolonged glucose deprivation and can establish a glucose deprivation-resistant (GDR) state characterized by sustained restoration of proliferation in the absence of glucose in the medium. Upon complete glucose deprivation, a fraction of cells dies, whereas the remaining population enters a senescence-like dormant state (Dorm) marked by growth arrest, elevated ROS, urea-cycle-associated metabolic remodeling, and accumulation of DNA damage. After approximately one month, a subset of these dormant cells acquires glucose-deprivation resistance and resumes proliferation in glucose-free medium. In the GDR state, cells maintain oxidative phosphorylation (OXPHOS) while establishing enhanced redox control associated with one-carbon, transsulfuration, and glutathione metabolism and reduced DNA-damage signaling. Functional perturbation of redox control, mitochondrial fatty-acid utilization, and PERK/ISR stress-response signaling impaired cell survival and/or long-term proliferative capacity, whereas antioxidant supplementation facilitated proliferative recovery of Dorm cells. GDR populations additionally underwent pronounced oligoclonal expansion during acquisition of the GDR phenotype. Collectively, these findings demonstrate that colorectal cancer cells can adapt to prolonged glucose deprivation by establishing a distinct metabolic and stress-adapted state oriented toward OXPHOS, redox control, and sustained proliferation.