英国剑桥癌症研究所Douglas J. Winton研究小组发现，多克隆性克服了Apc诱导肿瘤发生过程中的适应障碍。相关论文于2024年10月30日发表在《自然》杂志上。

据悉，肿瘤抑制因子APC的功能缺失突变是肠道肿瘤发生的前提。APC突变的肠干细胞通过分泌Wnt拮抗剂与邻近的野生型细胞竞争，这加速了突变体的固定和随后的快速克隆扩增。然而人类患者和小鼠模型中的多克隆肠肿瘤报告，似乎与这一过程相悖。

研究人员将多色系追踪与小鼠化学诱变结合起来，证明很大一部分肠道肿瘤起源于多克隆。多克隆肿瘤的结构由具有不同Apc突变和转录状态的亚克隆组成，其主要由KRAS和MYC信号的差异驱动。这些通路层面的变化伴随着癌症干细胞表型的明显差异。

值得注意的是，这些发现通过致癌Kras突变的引入得到证实，该突变主要导致单克隆肿瘤的形成。此外，多克隆肿瘤具有加速生长的能力，这表明多克隆性与肿瘤进展之间存在关联。这些发现共同表明克隆间相互作用，在非细胞自主途径诱导肿瘤发生中的作用，这种非细胞自主途径依赖于克隆间不同致癌途径的激活。

附：英文英文

Title: Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis

Author: Sadien, Iannish D., Adler, Sam, Mehmed, Shenay, Bailey, Sasha, Sawle, Ashley, Couturier, Dominique-Laurent, Eldridge, Matthew, Adams, David J., Kemp, Richard, Loureno, Filipe C., Winton, Douglas J.

Issue&Volume: 2024-10-30

Abstract: Loss-of-function mutations in the tumour suppressor APC are an initial step in intestinal tumorigenesis1,2. APC-mutant intestinal stem cells outcompete their wild-type neighbours through the secretion of Wnt antagonists, which accelerates the fixation and subsequent rapid clonal expansion of mutants3,4,5. Reports of polyclonal intestinal tumours in human patients and mouse models appear at odds with this process6,7. Here we combine multicolour lineage tracing with chemical mutagenesis in mice to show that a large proportion of intestinal tumours have a multiancestral origin. Polyclonal tumours retain a structure comprising subclones with distinct Apc mutations and transcriptional states, driven predominantly by differences in KRAS and MYC signalling. These pathway-level changes are accompanied by profound differences in cancer stem cell phenotypes. Of note, these findings are confirmed by introducing an oncogenic Kras mutation that results in predominantly monoclonal tumour formation. Further, polyclonal tumours have accelerated growth dynamics, suggesting a link between polyclonality and tumour progression. Together, these findings demonstrate the role of interclonal interactions in promoting tumorigenesis through non-cell autonomous pathways that are dependent on the differential activation of oncogenic pathways between clones.

DOI: 10.1038/s41586-024-08053-0

Source: https://www.nature.com/articles/s41586-024-08053-0