Cancer Research UK Beatson Institute, Glasgow, UK.
National Physical Laboratory, London, UK.
Nat Metab. 2023 Aug;5(8):1303-1318. doi: 10.1038/s42255-023-00857-0. Epub 2023 Aug 14.
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 Apc mice indicating its potential as a metabolic drug target in CRC.
结直肠癌（CRC）的基因组景观由肿瘤抑制因子如 APC 的失活突变和致癌突变如突变型 KRAS 塑造。在这里，我们使用基因工程小鼠模型和基于多模式质谱的代谢组学来研究 CRC 的常见遗传驱动因素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潜在的遗传改变对肠道组织进行分层，并用质谱成像来识别肿瘤、基质和正常相邻组织。通过鉴定驱动正常组织和转化组织之间变化的离子，我们发现蛋氨酸循环的失调是 APC 缺陷型 CRC 的一个标志。在小鼠肠道中缺失 Apc 足以驱动其一种酶，腺苷同型半胱氨酸酶（AHCY）的表达，在人类 CRC 中也发现其转录上调。靶向 AHCY 功能可损害体外 APC 缺陷型类器官的生长，并防止体内急性缺失 Apc 驱动的特征性过度增殖/隐窝祖细胞表型，即使在突变型 Kras 的情况下也是如此。最后，AHCY 的药理抑制减少了 Apc 小鼠的肠道肿瘤负担，表明其作为 CRC 代谢药物靶点的潜力。
