Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer
Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer
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DOI：
10.1038/s41467-019-08586-3
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发表时间：
2019-02-13
影响因子：
16.6
通讯作者：
Sansom, Owen J.
中科院分区：
文献类型：
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作者：
Gay, David M.;Ridgway, Rachel A.;Sansom, Owen J.
Wnt信号传导的不同阈值被认为驱动干细胞维持、再生、分化和癌症。然而，致癌Wnt信号传导可以特异性靶向的原则仍然存在争议。在这里，我们研究的需求BCL 9/9 l，Wnt增强体的成分，肠转化后的肿瘤抑制APC的损失。虽然需要Lgr 5+肠干细胞和再生，Bcl 9/9 l缺失对正常的肠道内稳态没有影响。BCL 9/9 l的丢失抑制了体内急性APC丢失和随后的Wnt途径失调的许多特征。这导致Wnt途径活化的水平有利于近端小肠（SI）中的肿瘤起始并阻断结肠中的肿瘤生长。此外，Bcl 9/9 l缺失完全消除了β-连环蛋白驱动的肠和肝细胞转化。我们推测这些结果支持Wnt驱动肿瘤形成的正确假设。重要的是，BCL 9/9 l的缺失在阻断结肠肿瘤发生和最类似于人类癌症中发生的突变方面特别有效。
Different thresholds of Wnt signalling are thought to drive stem cell maintenance, regeneration, differentiation and cancer. However, the principle that oncogenic Wnt signalling could be specifically targeted remains controversial. Here we examine the requirement of BCL9/9l, constituents of the Wnt-enhanceosome, for intestinal transformation following loss of the tumour suppressor APC. Although required for Lgr5+ intestinal stem cells and regeneration, Bcl9/9l deletion has no impact upon normal intestinal homeostasis. Loss of BCL9/9l suppressed many features of acute APC loss and subsequent Wnt pathway deregulation in vivo. This resulted in a level of Wnt pathway activation that favoured tumour initiation in the proximal small intestine (SI) and blocked tumour growth in the colon. Furthermore, Bcl9/9l deletion completely abrogated beta-catenin driven intestinal and hepatocellular transformation. We speculate these results support the just-right hypothesis of Wnt-driven tumour formation. Importantly, loss of BCL9/9l is particularly effective at blocking colonic tumourigenesis and mutations that most resemble those that occur in human cancer.