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: 10332898
• 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/10332898
• 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; Control Groups; Data; Databases; Disease; Dose; E-Cadherin; Enzyme-Linked Immunosorbent Assay; Fluorouracil; Genomics; Goals; Hepatotoxicity; Human; Immune; In Vitro; Investigation; Kidney; Ligands; Luciferases; 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; 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; Tumor Immunity; Tumor Volume; Tumor-infiltrating immune cells; United States; Vimentin; Xenograft procedure; base; beta catenin; beta-Chemokines; cancer cell; chemokine; chemokine receptor; chemotherapy; colon cancer patients; colon cancer treatment; conventional therapy; cytokine; cytotoxic; cytotoxicity; design; efficacious treatment; epithelial to mesenchymal transition; improved; in vivo; indexing; innovation; macrophage; migration; molecular phenotype; mouse model; neoplastic cell; novel; novel strategies; oxaliplatin; pre-clinical; prospective; response; screening; small molecular inhibitor; stemness; therapy outcome; transcriptome; 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.

翻译后摘要：结肠癌（CoCa）仍然是癌症相关死亡的第三大原因，因为 目前提供的治疗早期和晚期CoCa的化学治疗剂不能达到最佳的临床反应， 并且患者经常产生耐药性并遭受严重的毒性。因此，更有效的治疗选择 具有较低的毒性是改善CoCa临床结果的关键。为达致这个目标，我们建议 研究CC趋化因子受体6（CCR 6）及其配体CCL 20在细胞和分子生物学中的作用， 导致目前提供的化疗药物（5 FU和奥沙利铂）结局不良的机制， 开发更有效、毒性更低的治疗方法。拟议的调查是基于我们公布的， 初步数据显示（i）CoCa细胞和组织中CCR 6表达较高;（ii）CCR 6表达阳性 与疾病阶段相关;（iii）CCR 6/CCL 20具有生物学活性，并促进肿瘤细胞的迁移和侵袭。 （iv）CCR 6/CCL 20激活β-连环蛋白、Snail、波形蛋白、α-SMA并下调E-钙粘蛋白，表明 该轴在维持间充质表型中的重要性，已知对 化疗基于此，我们假设CCR 6-CCL 20轴支持细胞和分子生物学功能。 重编程以逃避化疗药物和开发针对CCR 6/CCL 20的治疗剂将改善 化疗效果将使用以下目标来检验假设。目标1：定义CCR 6- 介导的分子机制与不良化疗反应相关。在这一目标下， 使用基因组学和蛋白质组学方法，我们将确定CCR 6/CCL 20轴对 分子迂回癌细胞采取促进细胞和分子表型，帮助省略细胞毒性作用 常规化疗药物。此外，我们将确定阻断CCR 6/CCL 20轴是否会改善 5-FU和奥沙利铂在次优剂量下的细胞毒性。此外，使用临床样本，我们将建立 CCR 6/CCL 20对化疗反应影响。目的2：确定CCR 6抑制对细胞增殖的影响。 体内化疗反应。使用异种移植和同系小鼠模型，这一目的将确定 CCR 6/CCL 20轴抑制对5-FU和奥沙利铂体内疗效的影响。同基因模型 将使我们能够确定CCR 6/CCL 20抑制对全身和肿瘤免疫的影响， 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， 涉及改善化疗功效和器官毒性的机制。实现这一目标将 提供使用CCR 6/CCL 20定向治疗作为新治疗方式的原理。这一拟议 这项研究是新颖的，因为CCR 6/CCL 20对细胞和分子重编程的影响导致了不良的免疫反应。 5-FU和奥沙利铂的反应在体外和体内均未检测。本研究获得的信息将 在设计具有最小毒性的高效治疗组合方面具有重要意义。这种预期 治疗选择将改善CoCa临床结局和患者的生活质量。