The finding that CDK5-CREB1 enhances glioma stem cells and AMPK-CREB1 potentiates glioblastoma stem cells indicate the role of cAMP responsive program in stemness.21,22 A recent study in metastatic colorectal cancer confirms that cAMP-CREB1 signaling enhances cancer stemness.23 However, whether cancer cell acquires stemness through employing a TME neural signal dependent CRE program remains undetermined. The gene discussed is CREB1; the disease is metastatic colorectal cancer.