p53 terminates the regenerative fetal-like state after colitis-associated injury
Kimberly Hartl, Şafak Bayram, Alexandra Wetzel, Christine Harnack, Manqiang Lin, Anne‐Sophie Fischer, Lichao Liu, Giulia Beccaceci, Guido Mastrobuoni, Sabrina Geisberger, Martin Forbes, Benedict J.E. Monteiro, Martina Macino, Roberto E. Flores, Cornelius Engelmann, Hans‐Joachim Mollenkopf, Michael Schupp, Frank Tacke, Ashley D. Sanders, Stefan Kempa, Hilmar Berger, Michael Sigal
Abstract
Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a “fetal-like” regenerative state. Here, we use murine and organoid-based models to study the role of Trp53 during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack Trp53 remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, Trp53 deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated CRC.