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

doi:10.1126/sciadv.adp8783

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 KempaHilmar Berger, Michael Sigal

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Article number	eadp8783
Journal	Science advances
Volume	10
Issue number	43
DOIs	https://doi.org/10.1126/sciadv.adp8783
State	Published - 25 Oct 2024
Externally published	Yes

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Hartl, K., Bayram, Ş., Wetzel, A., Harnack, C., Lin, M., Fischer, A. S., Liu, L., Beccaceci, G., Mastrobuoni, G., Geisberger, S., Forbes, M., Monteiro, B. J. E., Macino, M., Flores, R. E., Engelmann, C., Mollenkopf, H. J., Schupp, M., Tacke, F., Sanders, A. D., ... Sigal, M. (2024). p53 terminates the regenerative fetal-like state after colitis-associated injury. Science advances, 10(43), Article eadp8783. https://doi.org/10.1126/sciadv.adp8783

@article{6536893cf3b042ce94040a901d7dfe0e,

title = "p53 terminates the regenerative fetal-like state after colitis-associated injury",

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.",

author = "Kimberly Hartl and {\c S}afak Bayram and Alexandra Wetzel and Christine Harnack and Manqiang Lin and Fischer, {Anne Sophie} and Lichao Liu and Giulia Beccaceci and Guido Mastrobuoni and Sabrina Geisberger and Martin Forbes and Monteiro, {Benedict J.E.} and Martina Macino and Flores, {Roberto E.} and Cornelius Engelmann and Mollenkopf, {Hans Joachim} and Michael Schupp and Frank Tacke and Sanders, {Ashley D.} and Stefan Kempa and Hilmar Berger and Michael Sigal",

note = "Publisher Copyright: Copyright {\textcopyright} 2024 The Authors, some rights reserved;",

year = "2024",

month = oct,

day = "25",

doi = "10.1126/sciadv.adp8783",

language = "English",

volume = "10",

journal = "Science advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

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Hartl, K, Bayram, Ş, Wetzel, A, Harnack, C, Lin, M, Fischer, AS, Liu, L, Beccaceci, G, Mastrobuoni, G, Geisberger, S, Forbes, M, Monteiro, BJE, Macino, M, Flores, RE, Engelmann, C, Mollenkopf, HJ, Schupp, M, Tacke, F, Sanders, AD, Kempa, S, Berger, H & Sigal, M 2024, 'p53 terminates the regenerative fetal-like state after colitis-associated injury', Science advances, vol. 10, no. 43, eadp8783. https://doi.org/10.1126/sciadv.adp8783

TY - JOUR

T1 - p53 terminates the regenerative fetal-like state after colitis-associated injury

AU - Hartl, Kimberly

AU - Bayram, Şafak

AU - Wetzel, Alexandra

AU - Harnack, Christine

AU - Lin, Manqiang

AU - Fischer, Anne Sophie

AU - Liu, Lichao

AU - Beccaceci, Giulia

AU - Mastrobuoni, Guido

AU - Geisberger, Sabrina

AU - Forbes, Martin

AU - Monteiro, Benedict J.E.

AU - Macino, Martina

AU - Flores, Roberto E.

AU - Engelmann, Cornelius

AU - Mollenkopf, Hans Joachim

AU - Schupp, Michael

AU - Tacke, Frank

AU - Sanders, Ashley D.

AU - Kempa, Stefan

AU - Berger, Hilmar

AU - Sigal, Michael

PY - 2024/10/25

Y1 - 2024/10/25

N2 - 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.

AB - 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.

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U2 - 10.1126/sciadv.adp8783

DO - 10.1126/sciadv.adp8783

M3 - Article

C2 - 39453996

AN - SCOPUS:85207738949

SN - 2375-2548

VL - 10

JO - Science advances

JF - Science advances

IS - 43

M1 - eadp8783

ER -

p53 terminates the regenerative fetal-like state after colitis-associated injury

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