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

结直肠癌中的 Myc - miR-17-92 轴

基本信息

批准号：
9251789
负责人：
Andrei Thomas-Tikhonenko
金额：
$ 38.43万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251789
关键词：
Alleles Alpha Cell Angiogenic Factor Antineoplastic Agents ApcMin/+ mice Attenuated Binding Blood Vessels Cell Nucleus Cells Clinical Trials Colon Colorectal Cancer Complement Factor B Complex Disease Disease Progression Down-Regulation Drug Targeting Drug resistance Elements Event Feedback Genes Genetic Transcription Genomics Goals Grant Human Hypervascular Individual Innovative Therapy KRAS2 gene Ligands MYC gene Measures Mediating MicroRNAs Modeling Mus Mutation Neoplasms in Vascular Tissue Paper Pathogenesis Pathway interactions Phenotype Publishing Resistance Role Signal Pathway Signal Transduction T cell factor 4 TGFBR1 gene Testing The Cancer Genome Atlas Thrombospondin 1 Transforming Growth Factor beta Transforming Growth Factors Tumor Suppressor Proteins WNT Signaling Pathway angiogenesis antiangiogenesis therapy beta catenin cancer genetics cancer genomics colon cancer cell line exhaustion genome-wide in vivo inhibitor/antagonist mimetics neovascularization new therapeutic target overexpression patient subsets predicting response pressure prevent public health relevance receptor response restoration small molecule targeted treatment tumor

项目摘要

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.