An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc- driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates c-Myc , a known Wnt target, which drives heightened glycolytic metabolism. Using patient-derived organoids, we show that circadian rhythms are lost in human tumors. Last, we identify that variance between core clock and Wnt pathway genes significantly predicts the survival of patients with CRC. Overall, our findings demonstrate a previously unidentified mechanistic link between clock disruption and CRC, which has important implications for young onset cancer prevention.

中文翻译：

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生物钟的破坏导致 Apc 杂合性丧失，加速结直肠癌的发生


据报道，年轻发病的结直肠癌 (CRC) 呈惊人上升趋势；然而，潜在的分子机制仍不清楚。年轻发病的结直肠癌的疑似危险因素包括环境因素，例如生活方式和饮食因素，这些因素已知会影响生物钟。我们发现生物钟的遗传破坏和环境破坏都会加速APC-驱动 CRC 体内发病机制。使用肠道类器官模型，我们证明时钟破坏通过驱动来促进转化阿普克杂合性丧失，从而过度激活 Wnt 信号传导。这上调了c-Myc ，一个已知的 Wnt 靶点，可促进糖酵解代谢。使用源自患者的类器官，我们发现人类肿瘤中昼夜节律丢失。最后，我们发现核心时钟和 Wnt 通路基因之间的差异可以显着预测 CRC 患者的生存率。总体而言，我们的研究结果证明了时钟中断与 CRC 之间存在先前未被识别的机制联系，这对预防年轻发病的癌症具有重要意义。