结肠直肠癌（CRC）的基因组景观受到肿瘤抑制基因（如APC）的非活性突变和致癌基因突变（如突变的KRAS）的影响。本研究使用基因工程小鼠模型和多模式质谱代谢组学，研究常见CRC遗传驱动因子对肠道代谢景观的影响。我们表明，非靶向代谢组学分析可用于根据基因改变对肠道组织进行分层，并使用质谱成像方法识别肿瘤、基质和正常相邻组织。通过识别驱动正常和转化组织差异的离子，我们发现甲硫氨酸循环的失调是APC缺陷型CRC的特征。在小鼠的肠道中发现Apc的丧失足以驱动其中一种酶，腺苷/同型半胱氨酸水解酶（AHCY）的表达，在人类CRC中也发现其转录上调。针对AHCY功能的靶向干扰阻碍了APC缺陷型器官样体外增长，并阻止了急性删除Apc所驱动的特征性高增殖/囊肿祖细胞表型，即使在突变的Kras状态下也是如此。最后，通过药物抑制AHCY减少ApcMin/+小鼠的肠道肿瘤负担，表明其作为CRC中代谢药物靶点的潜力。© 2023. 作者（们）。

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.© 2023. The Author(s).