Tissue-specific Roles of Axin in Canonical Wnt Signaling and Tumorigenesis

描述(申请人提供)：规范的Wnt信号异常会导致发育异常，Wnt信号的增加会导致多种肿瘤的形成，包括儿童髓母细胞瘤和绝大多数人类结直肠癌。这引起了人们对识别Wnt通路的小分子抑制剂用于治疗的相当大的兴趣。最近，有人建议通过稳定轴蛋白来抑制Wnt通路的小分子，如IWR-1和XAV939，将在治疗中发挥作用。Axin是Wnt途径的一个关键的负调控因子，因为它是β-连环蛋白破坏复合体的支架，在没有配体的情况下阻止该途径。我们最近发现，在发育过程中，通过突变或通过IWR-1处理来稳定Axin在某些茎/祖群体中具有促进Wnt信号的相反作用。这些发现提出了这样一种可能性，即典型的Wnt途径的电路在干细胞中是不同的。我们将验证这样的假设，即稳定的Axin可以通过促进Axin-LRP5/6膜复合体的形成来激活Wnt途径，从而增加游离？-连环蛋白的水平。我们将确定稳定的Axin蛋白影响的细胞类型特异性的机制。我们将使用遗传学方法在小鼠中鉴定Axin2蛋白稳定激活典型Wnt途径的其他细胞，重点放在肠、脑、乳房和皮肤中依赖Wnt的干细胞，这些干细胞可以作为癌症干细胞。绝大多数人类结直肠癌与Wnt途径的负调控因子APC的突变或沉默有关。我们将在小鼠ApcMin模型中测试Axin2稳定的等位基因是否抑制或促进肠道息肉的形成。这些研究将提供一个范例，说明干细胞/祖细胞在对Wnt途径抑制剂的敏感性方面与其他细胞的不同之处，这将确定适当的治疗靶点。

DESCRIPTION (provided by applicant): Abnormal canonical Wnt signaling causes developmental abnormalities and increased Wnt signaling drives the formation of a variety of tumors, including the childhood medulloblastoma and the vast majority of human colorectal carcinomas. This has generated considerable interest in the identification of small molecule inhibitors of the Wnt pathway for therapy. Recently, it has been suggested that small molecules that inhibit the Wnt pathway through stabilization of Axin, such as IWR-1 and XAV939, would be useful in therapy. Axin is a key negative regulator of the Wnt pathway because of its role as a scaffold of the ?-catenin destruction complex, which keeps the pathway off in the absence of ligand. We recently discovered that stabilization of Axin through either mutation or by treatment with IWR-1 has the opposite effect of promoting Wnt signaling in certain stem/progenitor populations during development. These findings raise the possibility that the circuitry of the canonical Wnt pathway is different in stem cells. We will test the hypothesis that stabilized Axin can activate the Wnt pathway by favoring the formation of an Axin-LRP5/6 membrane complex that increases the level of free ?-catenin. We will define the mechanisms responsible for the cell type specificity of the effects of stabilized Axin protein. We will use a genetic approach to identify other cells in the mouse where stabilization of Axin2 protein activates the canonical Wnt pathway, focusing on the Wnt-dependent stem cells in the intestine, brain, breast and skin that could act as cancer stem cells. The vast majority of cases of human colorectal carcinoma are associated with mutation or silencing of APC, a negative regulator of the Wnt pathway. We will test whether the stabilized allele of Axin2 suppresses or enhances intestinal polyp formation in the mouse ApcMin model. The studies will provide a paradigm for how stem/progenitor cells differ from other cells in their sensitivity to Wnt pathway inhibitors, which will define appropriae targets for therapy.