Role of CCR6-CCL20 in biology and chemotherapeutic response in colon cancer

CCR6-CCL20 在结肠癌生物学和化疗反应中的作用

• 批准号: 10598455
• 负责人: Hina Abdulrehman Mir
• 金额: $ 10.65万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598455
• 关键词: Apoptosis; Apoptotic; Bioinformatics; Biological; Biology; Biometry; Blood; Blood Chemical Analysis; CCL20 gene; Cancer Etiology; Cancer Model; Cell Cycle; Cell Line; Cessation of life; Chemoresistance; Clinic; Clinical; Colon Carcinoma; Combined Modality Therapy; Control Groups; Data; Databases; Disease; Dose; E-Cadherin; Enzyme-Linked Immunosorbent Assay; Fluorouracil; Genomics; Goals; Hepatotoxicity; Human; Immune; In Vitro; Invaded; Investigation; Kidney; Ligands; Luciferases; Macrophage; Maximum Tolerated Dose; Mediating; Mesenchymal; Modality; Modeling; Molecular; Molecular Target; Mus; Normal Cell; Organ; Outcome; Pathology; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Proliferating; Proteomics; Publications; Publishing; Quality of life; RNA Interference; Regulatory T-Lymphocyte; Research; Research Personnel; Resistance development; Role; Sampling; Serum; Signal Transduction; Snails; Spleen; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Toxic effect; Treatment Efficacy; Treatment-related toxicity; Tumor Immunity; Tumor Volume; Tumor-infiltrating immune cells; United States; Vimentin; Xenograft procedure; beta catenin; beta-Chemokines; cancer cell; chemokine; chemokine receptor; chemotherapy; colon cancer patients; colon cancer treatment; conventional therapy; cytokine; cytotoxic; cytotoxicity; design; efficacious treatment; efficacy evaluation; epithelial to mesenchymal transition; improved; in vivo; indexing; ineffective therapies; innovation; migration; molecular phenotype; mouse model; neoplastic cell; novel; novel strategies; oxaliplatin; pre-clinical; prospective; response; screening; small molecular inhibitor; stemness; therapy outcome; transcriptomic profiling; treatment group; treatment response; tumor; tumor xenograft

Abstract: Colon cancer (CoCa) remains the third leading cause of cancer-related deaths because chemotherapeutics currently offered to treat early and advanced CoCa fail to achieve optimal clinical response, and patients often develop resistance and suffer severe toxicity. Therefore, a more efficacious treatment option with lower toxicity is crucial to improve CoCa clinical outcomes. To achieve this objective, we propose investigating the role of CC chemokine receptor 6 (CCR6) and its ligand CCL20 on cellular and molecular mechanisms contributing to the poor outcome of currently offered chemotherapeutics (5FU and Oxaliplatin) and develop more effective and less toxic treatment. The proposed investigation is based on our published and preliminary data showing (i) higher CCR6 expression in CoCa cells and tissues; (ii) CCR6 expression positively correlates with disease stage; (iii) CCR6/CCL20 is biologically active and promotes migration and invasion of CoCa, (iv) CCR6/CCL20 activates β-catenin, Snail, vimentin, α-SMA and down regulates E-cadherin indicating the significance of this axis in maintaining mesenchymal phenotype known to be less responsive to chemotherapy. Based on this, we hypothesize that the CCR6-CCL20 axis supports cellular and molecular reprogramming to escape chemotherapeutics and developing therapeutics directed to CCR6/CCL20 will improve chemotherapeutic efficacy. The hypothesis will be tested using the following aims. Aim 1: Define the CCR6- mediated molecular mechanism(s) associated with the poor chemotherapeutic response. Under this aim, using genomics and proteomics approach, we will determine the impact of the CCR6/CCL20 axis on the molecular detour cancer cells take to promote cellular and molecular phenotypes that help omit cytotoxic effects of conventional chemotherapeutics. Additionally, we will ascertain if blocking CCR6/CCL20 axis will improve cytotoxicity of 5-FU and Oxaliplatin at a suboptimal dose. Further, using clinical samples, we will establish the impact of CCR6/CCL20 on chemotherapeutic response. Aim 2: Determine the effect of CCR6 inhibition on the chemotherapeutic response in vivo. Using xenograft and syngenic murine model, this aim will determine the impact of CCR6/CCL20 axis inhibition on the efficacy of 5-FU and Oxaliplatin in vivo. The syngenic model will allow us to ascertain the effects of CCR6/CCL20 inhibition on systemic and tumor immunity with or without 5-FU and Oxaliplatin. Endpoint analysis of tumor and serum will determine the alteration in cellular and molecular mechanisms involved in improving the chemotherapeutic efficacy and organ toxicity. Completing this aim will provide the rationale for using CCR6/CCL20 directed therapy as a new treatment modality. This proposed research is novel since the impact of CCR6/CCL20 on cellular and molecular reprogramming contributing to poor 5-FU and Oxaliplatin response is untested both in vitro and in vivo. Information obtained from this study will be significant in designing a highly efficacious treatment combination with minimal toxicity. This anticipated treatment option will improve CoCa clinical outcomes and patient’s quality of life.

摘要：结肠癌（COCA）仍然是与癌症相关死亡的第三主要原因，因为 目前提供的化学治疗剂可用于治疗早期和晚期可口可乐，无法实现最佳的临床反应， 患者经常会产生抗药性并遭受严重的毒性。因此，一个更有效的治疗选择 毒性较低对于改善可口可乐临床结果至关重要。为了实现这一目标，我们建议 研究CC趋化因子受体6（CCR6）及其配体CCL20对细胞和分子的作用 导致当前提供的化学治疗剂（5FU和Oxaliplatin）和 产生更有效和毒性更少的治疗方法。拟议的调查是基于我们发布的， 初步数据显示（i）可口可乐和组织中CCR6较高的表达； （ii）ccr6表达阳性 与疾病阶段相关； （iii）CCR6/CCL20具有生物活性，并促进了迁移和入侵 可口可乐，（iv）CCR6/CCL20激活β-catenin，蜗牛，波形蛋白，α-SMA和down，调节E-钙粘着蛋白，表明E-钙粘蛋白指示 该轴对维持间充质表型的重要性，已知对 化学疗法。基于此，我们假设CCR6-CCL20轴支持细胞和分子 重新编程以逃避化学治疗和开发针对CCR6/CCL20的疗法将改善 化学治疗效率。该假设将使用以下目的进行检验。目标1：定义CCR6-- 介导的分子机制与不良的化学治疗反应有关。在这个目标下， 使用基因组学和蛋白质组学方法，我们将确定CCR6/CCL20轴对 分子绕道癌细胞采取的促进细胞和分子表型有助于省略细胞毒性作用 常规化学治疗药。此外，我们将确定阻止CCR6/CCL20轴是否会改善 5-FU的细胞毒性和在次优剂量下的奥沙利铂。此外，使用临床样本，我们将建立 CCR6/CCL20对化学治疗反应的影响。目标2：确定CCR6抑制对 体内化学治疗反应。使用Xenographographic和Synngic Murine模型，此目标将决定 CCR6/CCL20轴抑制对体内5-FU和奥沙利铂效率的影响。合成模型 将使我们能够确定CCR6/CCL20抑制对有或没有的全身性和肿瘤免疫的影响 5-FU和奥沙利铂。肿瘤和血清的终点分析将确定细胞和分子的改变 提高化学治疗效率和器官毒性涉及的机制。完成这个目标 提供使用CCR6/CCL20定向疗法作为一种新的治疗方式的理由。这提出了 研究是新颖的，因为CCR6/CCL20对细胞和分子重编程的影响有助于差 在体外和体内未经测试的5-FU和奥沙利铂反应。从这项研究获得的信息将是 对于设计高效的治疗组合与最小毒性的结合很重要。这是预期的 治疗方案将改善可口可乐的临床结果和患者的生活质量。