Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
Sci Adv. 2024 Oct 25;10(43):eadp8783. doi: 10.1126/sciadv.adp8783.
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 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 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, 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.
缺乏 p53 信号的细胞在溃疡性结肠炎（UC）中经常出现，被认为是 UC 相关结直肠癌（CRC）的早期驱动因素。结肠炎期间的上皮损伤与成人、稳态的短暂干细胞重编程有关，使其向“胎儿样”再生状态转变。在这里，我们使用鼠类和类器官模型来研究在细胞上皮重编程过程中 p53 信号的作用。我们发现，p53 信号在稳态时是沉默且可有可无的，但在 DSS 诱导的结肠炎时，上皮细胞中 p53 信号强烈上调。虽然在 WT 细胞中，这会导致再生状态的终止，但缺乏 p53 的隐窝长期保持在高度增殖、再生状态。WT 细胞的再生状态需要高水平的 Wnt 信号来维持高水平的糖酵解。相反，由于限速酶 PKM2 的过度表达， 缺陷使 Wnt 独立的糖酵解成为可能。我们的研究揭示了 p53 信号在损伤诱导的再生状态下的具体的、依赖于背景的相关性，解释了在 UC 和 UC 相关 CRC 中缺乏 p53 信号的克隆大量存在的原因。
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