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

描述（由申请人提供）：异常典型Wnt信号传导导致发育异常，并且增加的Wnt信号传导驱动多种肿瘤的形成，包括儿童髓母细胞瘤和绝大多数人结直肠癌。这在鉴定用于治疗的Wnt途径的小分子抑制剂方面产生了相当大的兴趣。最近，有人提出，通过稳定Axin来抑制Wnt途径的小分子，如IWR-1和XAV 939，将可用于治疗。Axin是Wnt通路的一个关键负调节因子，因为它作为？连环蛋白破坏复合物，其在配体不存在的情况下保持通路关闭。我们最近发现，通过突变或用IWR-1处理来稳定Axin在发育期间在某些干/祖细胞群体中具有促进Wnt信号传导的相反效果。这些发现提高了经典Wnt通路的电路在干细胞中不同的可能性。我们将检验这样的假设，即稳定的Axin可以通过促进Axin-LRP 5/6膜复合物的形成来激活Wnt通路，该复合物增加游离的？连环蛋白。我们将定义负责稳定Axin蛋白的作用的细胞类型特异性的机制。我们将使用遗传学方法来鉴定小鼠中Axin 2蛋白稳定化激活经典Wnt通路的其他细胞，重点关注肠道，大脑，乳房和皮肤中可能充当癌症干细胞的Wnt依赖性干细胞。绝大多数人类结直肠癌病例与APC（Wnt通路的负调节因子）的突变或沉默相关。我们将在小鼠ApcMin模型中测试Axin 2的稳定化等位基因是否抑制或增强肠息肉形成。这些研究将为干/祖细胞在对Wnt通路抑制剂的敏感性方面如何不同于其他细胞提供一个范例，这将定义适当的治疗靶点。

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.