文章：

雷帕霉素挽救APC突变结肠类器官的分化

Rapamycin rescues APC-mutated colon organoid differentiation 

原文发布日期：2025-07-23 

英文摘要：

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by germline mutations in the adenomatous polyposis coli (APC) gene. This leads to numerous colorectal adenomas and a high risk of colorectal cancer (CRC). Our stem cell-derived colon organoid model revealed that a heterozygous APC mutation is sufficient to induce colorectal cancer formation. We found a link between APC mutation type, organoid maturation and FAP severity. Here, we show that severe germline mutations in hESCs employ diverse mechanisms of carcinogenesis. FAP1-hESCs expressing a truncated 332-amino acid protein exhibited a hyperactivated mTOR pathway, including PTEN inactivation and increased S6K1 and eIF4E activation. This affected oncogenic c-Myc expression and contributed to apoptosis resistance. Rapamycin treatment restored differentiation potential in FAP1 organoids but not FAP2 organoids, which expressed a larger truncated protein without mTOR pathway activation. Our in vitro colon organoids system findings were validated in human patients. Notably, a colon from a FAP1 patient exhibited high expression of mTOR pathway proteins. These findings highlight the potential of rapamycin for personalized therapy in FAP patients with distinct mTOR-mediated APC mutations. Our colon organoid model is valuable for studying CRC and developing new diagnostic, preventive, and therapeutic approaches to prevent or delay tumorigenesis in FAP patients. 

摘要翻译：

家族性腺瘤性息肉病（FAP）是一种常染色体显性遗传疾病，由腺瘤性息肉病（APC）基因的种系突变引发。该疾病会导致大量结直肠腺瘤并显著增加结直肠癌（CRC）风险。我们的干细胞源性结肠类器官模型显示，杂合性APC突变足以诱导结直肠癌形成。研究发现APC突变类型、类器官成熟度与FAP严重程度存在关联。本研究证实，人胚胎干细胞（hESCs）中的严重种系突变通过多种机制参与致癌过程：表达332个氨基酸截短蛋白的FAP1-hESCs表现出mTOR通路过度激活，包括PTEN失活以及S6K1和eIF4E激活增强，这影响了致癌蛋白c-Myc的表达并导致细胞抗凋亡能力增强。雷帕霉素治疗可恢复FAP1类器官的分化潜能，但对不激活mTOR通路、表达更大截短蛋白的FAP2类器官无效。我们的体外结肠类器官研究结果在患者组织中得到验证—— notably，FAP1患者的结肠组织显示mTOR通路蛋白高表达。这些发现表明，雷帕霉素对于具有不同mTOR介导型APC突变的FAP患者具有个性化治疗潜力。我们的结肠类器官模型为研究结直肠癌、开发新型诊断、预防和治疗策略以阻止或延缓FAP患者肿瘤发生提供了重要平台。

原文链接：

Rapamycin rescues APC-mutated colon organoid differentiation