CXCR4 as a target for colon cancer chemoprevention

CXCR4作为结肠癌化学预防的靶点

基本信息

批准号：
9803386
负责人：
Bruce Marc Bissonnette
金额：
$ 39.29万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9803386
关键词：
ATAC-seq Adoption Animal Model Azoxymethane Biological Assay Biological Availability CXCL12 gene CXCR4 Receptors CXCR4 gene Cancer Etiology Cancer Model Cessation of life Chemoprevention Chemopreventive Agent Chromatin Chromatin Structure Clinical Trials Colon Carcinoma Colonic Neoplasms Colorectal Cancer Consumption Cytokine Receptors DNA Methylation Data Development Diet Enzymes Epidermal Growth Factor Receptor Epigenetic Process Experimental Models Gene Expression Regulation Genetic Genetic Transcription Growth Histones Human In Vitro Incidence Individual Libraries Ligand Binding Ligands Malignant - descriptor Malignant Neoplasms Measures Migration Assay Modeling Mucous Membrane Mus Mutate Natural Products Neoplasm Metastasis Organoids Peptide Hydrolases Pharmacology Phase Population Premalignant Receptor Activation Receptor Signaling Regulation Reporter Role Signal Transduction Testing Toxic effect Tumor Burden Tumor Promotion Up-Regulation base cancer cell cancer chemoprevention chemokine receptor chemotherapy chromatin immunoprecipitation colorectal cancer prevention colorectal cancer risk histone modification inhibitor/antagonist insight mouse model nano novel novel strategies receptor recruit seal transcription factor transcriptome sequencing tumor tumor progression tumorigenesis western diet

项目摘要

PROJECT SUMMARY The risk of colorectal cancer (CRC) is substantially higher in populations consuming Western diets (WDs) and animal models confirm this association. WD-induced tumor promotion requires epidermal growth factor receptor (EGFR) signals that are driven by increased EGFR ligands. EGFR ligand release is controlled by proteinase ADAM17. Colonocyte deletion or pharmacological blockade of ADAM17 suppressed tumorigenesis. Chemokine receptor CXCR4 is expressed on colonocytes up-regulated with cancer progression and can activate ADAM17. The role of CXCR4 in diet-promoted tumorigenesis has not been elucidated. We found that WD up-regulated both CXCR4 and its ligand Sdf1α (aka CXCL12) in colonic mucosa. Together, these data suggest that CXCR4 is a targetable upstream regulator of WD-promoted tumor development by signaling transactivated colon cancer cell EGFR via an ADAM17-dependent mechanism. While CXCR4 is rarely mutated in cancer, its expression is up-regulated by transcription factors (TFs) and epigenetic changes, further evidence that factors such as diet regulate its activity. In preliminary studies, MSX-122, a CXCR4 inhibitor well tolerated in clinical trials, reduced colon tumor incidence by nearly 70% in azoxymethane (AOM)-treated Apc+/Min mice. Moreover, mice deleted of colonocyte CXCR4 developed fewer tumors than CXCR4+/+ mice on an Apc-deficient background. We hypothesize that CXCR4 is required for WD-promoted tumorigenesis, and that natural product (NP) inhibition of CXCR4 is a promising chemopreventative strategy. Studies that dissect CXCR4 regulation and effector signals and identify novel NP inhibitors could converge to uncover new targets for CRC prevention. To study the role of CXCR4 in tumor promotion by WDs and identify novel inhibitors, we propose three specific aims: Aim 1 To determine if CXCR4 activity is required for WD-promoted tumorigenesis. 1a)To assess the ability of CXCR4 inhibitor MSX-122 to suppress AOM tumorigenesis. We will compare MSX effects in Std diet and WD in premalignant and malignant phases and assess effector signals by RNAseq and EGFR activation. 1b) To genetically assess the role of CXCR4 in CRC, comparing colonocyte null CXCR4Δ/Δ mice to CXCR4+/Δ and CXCR4+/+ mice (all on Apc deficient background) and measure end points described in aim 1a. Aim 2a: To determine effects WD and neoplastic progression on TFs and histone modifications regulating Sdf1α and CXCR4 locally using ChIP assays and assess global effects of diet and tumorigenesis using chromatin ATAC-seq and DNA methylation by nano-5hmC-seal using organoids from conditional Apc-CXCR4 model. 5mC and 5hmC signals discovered globally, for example, regulate local histone modifications. 2b) To assess Sdf1α- CXCR4 gene regulation and effector signals in human colonic tumorigenesis using organoids as in 2a. Aim 3a To screen NP libraries for CXCR4 inhibitory activity. CXCR4 reporter assays (Ca2+ transients, migration assays and ligand-binding) will be used to confirm computationally predicted NP hits 3b Promising agents identified in aim3a will be prioritized and tested for chemopreventive efficacy in mouse models.

项目概要食用西方饮食 (WD) 的人群患结直肠癌 (CRC) 的风险要高得多动物模型证实了WD诱导的肿瘤促进需要表皮生长因子受体。由 EGFR 配体释放增加驱动的 (EGFR) 信号由蛋白酶控制。 ADAM17。结肠细胞缺失或 ADAM17 的药理学阻断可抑制趋化因子。受体 CXCR4 在结肠细胞上表达，随着癌症进展而上调，并且可以激活 ADAM17。我们发现 CXCR4 在饮食促进的肿瘤发生中的作用尚未阐明。 CXCR4 及其配体 Sdf1α（又名 CXCL12）均存在于结肠粘膜中，这些数据表明 CXCR4 存在。是 WD 促进肿瘤发展的靶向上游调节因子，通过信号传导反式激活结肠虽然 CXCR4 在癌症中很少发生突变，但它通过 ADAM17 依赖性机制调节癌细胞 EGFR。转录因子（TF）和表观遗传变化上调表达，进一步证明因子初步研究表明，CXCR4抑制剂MSX-122在临床上具有良好的耐受性。试验表明，氧化偶氮甲烷 (AOM) 治疗的 Apc+/Min 小鼠的结肠肿瘤发病率降低了近 70%。删除结肠细胞 CXCR4 的小鼠比 Apc 缺陷的 CXCR4+/+ 小鼠产生更少的肿瘤我们认为 CXCR4 是 WD 促进的肿瘤发生所必需的，并且是自然的。 CXCR4 的产物 (NP) 抑制是一种有前途的化学预防策略，对 CXCR4 进行了深入研究。调控和效应信号并识别新型 NP 抑制剂可以共同发现 CRC 的新靶标为了研究 CXCR4 在 WD 促进肿瘤中的作用并鉴定新型抑制剂，我们建议。三个具体目标：目标 1 确定 CXCR4 活性是否是 WD 促进的肿瘤发生所必需的。评估 CXCR4 抑制剂 MSX-122 抑制 AOM 肿瘤发生的能力我们将比较 MSX 的效果。在癌前和恶性阶段的标准饮食和 WD 中，并通过 RNAseq 和 EGFR 评估效应信号 1b) 为了从遗传学角度评估 CXCR4 在 CRC 中的作用，将结肠细胞缺失 CXCR4Δ/Δ 小鼠与结肠细胞缺失小鼠进行比较。 CXCR4+/Δ 和 CXCR4+/+ 小鼠（均处于 Apc 缺陷背景）并测量目标 1a 中描述的终点。目标 2a：确定 WD 和肿瘤进展对调节 Sdf1α 的 TF 和组蛋白修饰的影响和 CXCR4 局部使用 ChIP 检测，并使用染色质评估饮食和肿瘤发生的整体影响使用来自条件 Apc-CXCR4 模型的类器官通过 nano-5hmC-seal 进行 ATAC-seq 和 DNA 甲基化。例如，全球发现的 5hmC 信号调节局部组蛋白修饰 2b) 评估 Sdf1α-。使用类器官研究人类结肠肿瘤发生中的 CXCR4 基因调控和效应信号，如 2a 所示。目标 3a 筛选 NP 文库的 CXCR4 抑制活性（Ca2+ 瞬变、迁移）。分析和配体结合）将用于确认计算预测的 NP 命中 3b 有前途的药物目标3a中确定的基因将被优先考虑并在小鼠模型中测试其化学预防功效。