p53 terminates the regenerative fetal-like state after colitis-associated injury
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 <i>Trp53</i> 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 <i>Trp53</i> 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, <i>Trp53</i> 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.
Authors
- Christine Harnack (ORCID: https://orcid.org/0000-0003-0067-4921)
- Hilmar Berger (ORCID: https://orcid.org/0000-0002-6304-4946)
- Anne‐Sophie Fischer (ORCID: https://orcid.org/0000-0002-2176-1779)
- Martin Forbes (ORCID: https://orcid.org/0000-0001-7775-8352)
- Giulia Beccaceci (ORCID: https://orcid.org/0000-0002-6453-3725)
- Manqiang Lin (ORCID: https://orcid.org/0000-0003-4093-9277)
- Şafak Bayram (ORCID: https://orcid.org/0009-0009-5245-5473)
- Benedict J.E. Monteiro (ORCID: https://orcid.org/0000-0001-9718-2776)
- Hans‐Joachim Mollenkopf (ORCID: https://orcid.org/0000-0003-1167-4783)
- Cornelius Engelmann (ORCID: https://orcid.org/0009-0006-3813-7397)
- Kimberly Hartl (ORCID: https://orcid.org/0000-0002-2965-0512)
- Ashley D. Sanders (ORCID: https://orcid.org/0000-0003-3945-0677)
- Martina Macino (ORCID: https://orcid.org/0000-0002-8730-9005)
- Sabrina Geisberger (ORCID: https://orcid.org/0000-0001-6477-1312)
- Stefan Kempa (ORCID: https://orcid.org/0000-0002-0696-9299)
- Roberto E. Flores (ORCID: https://orcid.org/0000-0001-6500-8407)
- Michael Schupp (ORCID: https://orcid.org/0000-0003-3720-1052)
- Michael Sigal (ORCID: https://orcid.org/0000-0003-4772-0761)
- Alexandra Wetzel
- Guido Mastrobuoni (ORCID: https://orcid.org/0000-0003-4509-1295)
- Frank Tacke (ORCID: https://orcid.org/0000-0001-6206-0226)
- Lichao Liu (ORCID: https://orcid.org/0000-0002-9553-5475)
Institutions
- Max Delbrück Center (DE)
- Humboldt-Universität zu Berlin (DE)
- Max Planck Institute for Infection Biology (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-25
- DOI
- https://doi.org/10.1126/sciadv.adp8783
- Citations
- 12
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 3.39