Wnt signalling is a bi-directional vulnerability of cancer cells.
Wnt signalling is a bi-directional vulnerability of cancer cells.
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DOI：
10.18632/oncotarget.11203
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发表时间：
2016-09-13
期刊：
影响因子：
--
通讯作者：
Kolch W
中科院分区：
文献类型：
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作者：
Duffy DJ;Krstic A;Schwarzl T;Halasz M;Iljin K;Fey D;Haley B;Whilde J;Haapa-Paananen S;Fey V;Fischer M;Westermann F;Henrich KO;Bannert S;Higgins DG;Kolch W
Wnt信号传导参与多种癌症的形成、转移和复发。然而，关于该途径的激活或抑制是否最有希望作为癌症的治疗方法，存在持续的争论，各种肿瘤类型的证据相互矛盾。我们发现Wnt/β-catenin信号传导是神经母细胞瘤、恶性黑色素瘤和结直肠癌的双向脆弱性，即使在相同的癌症类型中，该通路的过度激活或抑制也代表了一种有前途的治疗策略。超活化指导癌细胞经历凋亡，甚至在由β-连环蛋白致癌驱动的细胞中。Wnt抑制阻断癌细胞增殖并促进神经母细胞瘤分化。Wnt和视黄酸共同治疗协同作用，代表了MYCN扩增的神经母细胞瘤的有希望的组合治疗。此外，我们报告了MYCN和β-catenin信号传导之间的新的交叉对话，其抑制正常的β-catenin介导的转录调节。β-连环蛋白靶基因特征可以预测患者的预后，其DNA结合伴侣TCF/LEF的表达水平也可以预测患者的预后。这种β-连环蛋白特征提供了一种工具，用于识别可能受益于Wnt导向治疗的神经母细胞瘤患者。总之，我们表明Wnt/β-连环蛋白信号传导是许多癌症实体的双向脆弱性，并且可能是恶性细胞的更广泛的保守特征。
Wnt signalling is involved in the formation, metastasis and relapse of a wide array of cancers. However, there is ongoing debate as to whether activation or inhibition of the pathway holds the most promise as a therapeutic treatment for cancer, with conflicting evidence from a variety of tumour types. We show that Wnt/β-catenin signalling is a bi-directional vulnerability of neuroblastoma, malignant melanoma and colorectal cancer, with hyper-activation or repression of the pathway both representing a promising therapeutic strategy, even within the same cancer type. Hyper-activation directs cancer cells to undergo apoptosis, even in cells oncogenically driven by β-catenin. Wnt inhibition blocks proliferation of cancer cells and promotes neuroblastoma differentiation. Wnt and retinoic acid co-treatments synergise, representing a promising combination treatment for MYCN-amplified neuroblastoma. Additionally, we report novel cross-talks between MYCN and β-catenin signalling, which repress normal β-catenin mediated transcriptional regulation. A β-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This β-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/β-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.