The Myc - miR-17-92 axis in colorectal cancers

 描述(申请人提供)：尽管结直肠癌(CRC)是癌症遗传学和最近的基因组学的最初试验场，但它仍然是一种致命的疾病。缺乏重大突破的一个原因是，关注单个信号通路不足以理解这种疾病的发病机制和进展。MYC癌基因就是一个很好的例子。它参与了数量惊人的功能相互作用，其中很少有被完全理解或充分验证的。这笔赠款的首要目标是确定可以作为治疗靶点的MYC途径相互作用。在结直肠癌中，由于WNT通路的激活突变，MYC经常过度表达。WNT配体与辅助受体FZD和LRP的结合可阻止APC肿瘤抑制因子介导的连环蛋白的降解。稳定的B-catenin转位到细胞核，在那里它与TCF4转录因子形成复合体，并驱动MYC的表达。然而，什么非突变事件有助于WNT依赖的Myc激活在很大程度上仍不清楚。MYC在高度遗传复杂性的CRC中的作用也没有得到确凿的证实。我们最近证实，MYC赋予CRC细胞一种血管丰富的表型。这是通过下调血栓反应蛋白-1(TSP1)和相关的抗血管生成因子来实现的，其中许多通常是由转化生长因子ç维持的。转化生长因子途径在结直肠癌中也经常失活，但它如何通过非突变方式进行调节仍有待观察。在过去的几年里，我们发现Myc远不是WNT和转化生长因子B信号的被动下游效应者，它有可能深刻地影响这两条途径。这在很大程度上是由于Myc能够上调miR-17~92 microRNA簇(又名。OncomiR-1)。与这一建议相关的是，在CRC中，miR-17-92直接针对和下调TSP1，但影响更广泛--转化生长因子途径的几个关键组成部分。另一个相关的Myc|miR-17~92靶点是抑制LRP配体和WNT信号抑制因子DKK3。这些发现导致了以下总体假设：WNT、Myc和miR-17~92形成了一个以前未被认识的正反馈环，它抑制了转化生长因子？信号转导，促进了肿瘤新生血管的形成。在这项建议中，我们的目标是：1.确定DKK3在维持Myc表达中的作用；2.确定Wnt|Myc|miR-17~92在克服转化生长因子ç抑制血管生成方面的作用；3.验证以WNT途径为靶点的药物耐药的决定因素--转化生长因子？在实现了这项提案的三个目标后，我们将重新绘制人类结直肠癌的接线图，确定治疗抗血管生成的新靶点，并利用癌症基因组学的力量来预测针对WNT和转化生长因子途径的新药的反应。

 DESCRIPTION (provided by applicant): Despite serving as the initial testing ground for cancer genetics and more recently - genomics, colorectal cancer (CRC) remains a deadly disease. One reason for the lack of major breakthroughs is that focusing on individual signaling pathways is not enough to understand pathogenesis and progression of this disease. The MYC oncogene is a case in point. It is involved in a dizzying number of functional interactions, few of which have been fully understood or sufficiently validated. The overarching goal of this grant is to identify MYC pathway interactions that can be targeted therapeutically. In CRC, MYC is frequently overexpressed due to activating mutations in the WNT pathway. Binding of WNT ligands to the co-receptors FZD and LRP prevents APC tumor suppressor-mediated degradation of ß-catenin. Stabilized ß-catenin translocates into the nucleus, where it forms a complex with the TCF4 transcription factor and drives MYC expression. However, what non-mutational events aid WNT-dependent Myc activation remains largely unknown. Nor has MYC function in highly genetically complex CRC been firmly established. We recently demonstrated that MYC confers upon CRC cells a hypervascular phenotype. This occurs through down-regulation of thrombospondin-1 (Tsp1) and related anti-angiogenic factors, many of which are normally sustained by transforming growth factor ß. The TGFß pathway, too, is frequently inactivated in CRC, but how it is regulated by non-mutational means remained to be seen. In the past several years we discovered that far from being a passive downstream effector of WNT and TGFß signaling, Myc has the potential to profoundly influence both pathways. This is due in large part to the ability o Myc to up-regulate the miR-17~92 microRNA cluster (a.k.a. oncomir-1). Of relevance to this proposal, in CRC miR-17-92 directly targets and down-regulates Tsp1, but with even broader impact - several key components of the TGFß pathway. Another relevant Myc | miR-17~92 target is DKK3, an inhibitory LRP ligand and WNT signaling suppressor. These discoveries have led to the following overall hypothesis: WNT, Myc, and miR-17~92 form a previously unrecognized positive feedback loop, which suppresses TGFß signaling and promotes tumor neovascularization. In this proposal, we aim to: 1. Define a role of DKK3 in sustaining Myc expression; 2. Determine the role of Wnt | Myc | miR-17~92 in overcoming angiogenesis suppression by TGFß; 3. Validate TGFß pathway mutations as determinants of resistance to drugs targeting the WNT pathway. After fulfilling the three Aims of this proposal we will have re-drawn the wiring diagrams of human CRC, identified novel targets for therapeutic anti-angiogenesis, and harnessed the power of cancer genomics to predict responses to new drugs targeting WNT and TGFß pathways.