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BCL9/9l 的缺失抑制了重现人类癌症的模型中的 Wnt 驱动的肿瘤发生。

Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer.

机构信息

Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.

Academic Medical Center (AMC), University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands.

出版信息

Nat Commun. 2019 Feb 13;10(1):723. doi: 10.1038/s41467-019-08586-3.

DOI:10.1038/s41467-019-08586-3
PMID:30760720
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6374445/
Abstract

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 β-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.

摘要

不同的 Wnt 信号阈值被认为可以驱动干细胞的维持、再生、分化和癌症。然而，致癌 Wnt 信号可以被特异性靶向的原则仍然存在争议。在这里，我们研究了 Wnt 增强子的组成部分 BCL9/9l 在 APC 肿瘤抑制因子缺失后引发肠道转化的需求。尽管 BCL9/9l 缺失对于 Lgr5+肠道干细胞和再生是必需的，但它对正常肠道稳态没有影响。BCL9/9l 的缺失抑制了体内 APC 缺失和随后 Wnt 通路失调的许多特征。这导致了 Wnt 通路激活的水平有利于近端小肠 (SI) 的肿瘤起始，并阻止了结肠的肿瘤生长。此外，BCL9/9l 的缺失完全阻断了β-catenin 驱动的肠道和肝细胞转化。我们推测这些结果支持 Wnt 驱动肿瘤形成的恰到好处假说。重要的是，BCL9/9l 的缺失特别有效地阻断了结肠肿瘤的发生，并且其突变最类似于人类癌症中发生的突变。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/fa3bcaf356f2/41467_2019_8586_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/a0df966acb83/41467_2019_8586_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/58a76277778d/41467_2019_8586_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/6d666976bc86/41467_2019_8586_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/32472b4947b3/41467_2019_8586_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/042ff93f73d4/41467_2019_8586_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/f82b355602a3/41467_2019_8586_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/ec06d27dbf7a/41467_2019_8586_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/fa3bcaf356f2/41467_2019_8586_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/a0df966acb83/41467_2019_8586_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/58a76277778d/41467_2019_8586_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/6d666976bc86/41467_2019_8586_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/32472b4947b3/41467_2019_8586_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/042ff93f73d4/41467_2019_8586_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/f82b355602a3/41467_2019_8586_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/ec06d27dbf7a/41467_2019_8586_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ce0/6374445/fa3bcaf356f2/41467_2019_8586_Fig8_HTML.jpg

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