工程化小鼠结直肠癌类器官揭示突变累积与顺序对肿瘤起始的影响
Impacts of mutation accumulation and order on tumor initiation revealed by engineered murine colorectal cancer organoids
利用小鼠肠道类器官按不同顺序引入 Kras、Apc 和 Trp53 驱动突变，发现突变累积在体外和体内模型中均带来生长优势，且突变顺序会影响类器官的致瘤特性。Trp53 缺失发生在 Apc 失活之前或之后的类器官，在体外表型和免疫缺陷小鼠中的致瘤性相似；但 Trp53 缺失先于 Apc 失活的类器官在免疫健全小鼠中成瘤潜力降低，可能与其独特的免疫特征有关。该研究提示有序的突变累积在结直肠癌起始中起关键作用，并可能具有临床意义。
来源：eLife · doi.org
Tumorigenesis typically follows a multi-hit trajectory, driven by accumulating oncogenic mutations. Colorectal cancer (CRC) has long served as a paradigmatic model of multi-hit tumorigenesis, characterized by adenoma-carcinoma transition accompanied by acquisition of specific oncogene and tumor suppressor mutations. However, how the temporal order of early mutations influences CRC initiation remains poorly understood. To address this, we established a CRC tumorigenesis model using murine intestinal organoids. By introducing defined combinations of key CRC driver mutations ( Kras , Apc , and Trp53 ) in distinct orders, we systematically investigated how the order of mutation accumulation affects tumor initiation. Our results reveal that the mutation accumulation confers growth advantages in both in vitro and in vivo models. Strikingly, mutation order also influenced the tumorigenic properties of the organoids. Whereas organoids with Trp53 loss before or after Apc loss similarly affected organoid phenotypes in vitro or tumorigenicity in immunodeficient mice, organoids with Trp53 loss preceding Apc inactivation exhibited reduced tumor-forming potential in immunocompetent mice, likely due to their distinct immunological features. Collectively, our study reveals a critical role of ordered mutation accumulation in CRC initiation, an insight that may hold clinical relevance.