A reversible metabolic stress-sensitive regulation of CRMP2A orchestrates EMT/stemness and increases metastatic potential in cancer

An epithelial-to-mesenchymal transition (EMT) phenotype with cancer stem cell-like properties is a critical feature of aggressive/metastatic tumors, but the mechanism(s) that promote it and its relation to metabolic stress remain unknown. Here we show that Collapsin Response Mediator Protein 2A (CRMP2A) is unexpectedly and reversibly induced in cancer cells in response to multiple metabolic stresses, including low glucose and hypoxia, and inhibits EMT/stemness. Loss of CRMP2A, when metabolic stress decreases (e.g., around blood vessels in vivo) or by gene deletion, induces extensive microtubule remodeling, increased glutamine utilization toward pyrimidine synthesis, and an EMT/stemness phenotype with increased migration, chemoresistance, tumor initiation capacity/growth, and metastatic potential. In a cohort of 27 prostate cancer patients with biopsies from primary tumors and distant metastases, CRMP2A expression decreases in the metastatic versus primary tumors. CRMP2A is an endogenous molecular brake on cancer EMT/stemness and its loss increases the aggressiveness and metastatic potential of tumors. [Display omitted] •CRMP2A is reversibly induced in response to diverse metabolic stressors•CRMP2A induction prevents acquisition of an energetically demanding EMT/stem cell state•Loss of CRMP2A when metabolic stress is reversed promotes EMT/stemness in cancer CRMP2A, a microtubule-associated protein, plays an unexpected role in the regulation of the EMT/stemness propensity of cancer cells. Boukouris et al. show how, in response to multiple metabolic stresses, changes in the relative levels of total and phosphorylated CRMP2A induce a reversible microtubule/cytoskeletal and metabolic remodeling, promoting EMT/stemness, migration, metastasis, and chemoresistance.