Morgan Ryan, Bayat Tork Mohammad Amin, Lin Zitong, Wild Claire, Frietze Luke R, Huang Sihao, Roh Meejeon, Olivas Andrea, Steele Colin W, Pan Tao, Shogan Benjamin D
Department of Surgery, University of Chicago, Chicago, IL, USA.
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
Cancer Lett. 2025 Jul 22;631:217943. doi: 10.1016/j.canlet.2025.217943.
The development of postoperative recurrent tumors or metastasis following surgical resection of colorectal cancer remains a major obstacle to colon cancer cure. While a high-fat diet is a risk factor for the development of recurrence, studies that examine the molecular mechanism by which diet drives postoperative tumors have been lacking. Here, using a murine model that mimics postoperative tumor formation, we show that the tumorigenic influence of a high-fat diet strongly depends on the genetic backbone of the primary tumor cells. We identify deoxycholic acid as a major contributor to the promotion of tumor recurrence only when the primary cancer cell has an APC-driving mutation. We investigate the deoxycholic acid effect on the proliferation of organoids and identify the organoid response to deoxycholic acid treatment, including the transcriptome expression and transfer RNA abundance, modification, and charging. The integrated analysis of mRNA and tRNA sequencing results reveals enhanced decoding of codons in proliferation-promoting genes. Our results provide a new understanding of how both diet and tumor genetics together lead to postoperative colorectal cancer recurrence.
结直肠癌手术切除后复发性肿瘤的发生或转移仍然是结肠癌治愈的主要障碍。虽然高脂肪饮食是复发的一个风险因素，但此前缺乏研究来探究饮食驱动术后肿瘤形成的分子机制。在此，我们使用一种模拟术后肿瘤形成的小鼠模型，发现高脂肪饮食的致瘤影响很大程度上取决于原发性肿瘤细胞的基因背景。我们确定，仅当原发性癌细胞存在APC驱动突变时，脱氧胆酸才是促进肿瘤复发的主要因素。我们研究了脱氧胆酸对类器官增殖的影响，并确定了类器官对脱氧胆酸治疗的反应，包括转录组表达以及转运RNA的丰度、修饰和负载。对mRNA和tRNA测序结果的综合分析揭示了促增殖基因中密码子解码的增强。我们的研究结果为饮食和肿瘤遗传学如何共同导致结直肠癌术后复发提供了新的认识。
