Human colon cancer cell lines, preclinical intestinal epithelial-specific GATOR1 and GATOR2 knockout mice subjected to colitis-induced or sporadic colon tumor models, small interfering RNA screening targeting regulators of mTORC1, and tissues of patients with CRC were used to assess the role of amino acid sensing in CRC.
We identified loss-of-function mutations of the GATOR1 complex in CRC and showed that altered expression of amino acid-sensing pathways predicted poor patient outcomes. We showed that dysregulated amino acid-sensing induced mTORC1 activation drives colon tumorigenesis in multiple mouse models. We found amino acid-sensing pathways to be essential in the cellular reprogramming of chemoresistance, and chemotherapeutic-resistant patients with colon cancer exhibited de-regulated amino acid sensing. Limiting amino acids in in vitro and in vivo models (low-protein diet) reverted drug resistance, revealing a metabolic vulnerability.
Our findings suggest a critical role for amino acid-sensing pathways in driving CRC and highlight the translational implications of dietary protein intervention in CRC.
方法:人结肠癌细胞系,临床前肠上皮特异性GATOR1和GATOR2基因敲除小鼠接受结肠炎诱导或散发性结肠肿瘤模型,小干扰RNA筛选靶向mTORC1调节因子和CRC患者组织用于评估氨基酸传感在CRC中的作用.
结果:我们确定了CRC中GATOR1复合体的功能缺失突变,并显示氨基酸感应通路表达的改变预测患者预后不良。我们表明,在多种小鼠模型中,失调的氨基酸感应诱导的mTORC1激活驱动结肠肿瘤发生。我们发现氨基酸传感途径在细胞重编程的化学抗性中至关重要,和化疗耐药的结肠癌患者表现出下调的氨基酸传感。限制氨基酸在体外和体内模型(低蛋白饮食)逆转耐药性,揭示了新陈代谢的脆弱性。
结论:我们的研究结果表明氨基酸感应通路在驱动CRC中的关键作用,并强调了饮食蛋白质干预在CRC中的翻译意义。