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）仍然是癌症相关死亡的第三大原因，因为 目前用于治疗早期和晚期 CoCa 的化疗药物未能达到最佳的临床反应， 患者常常会产生耐药性并遭受严重的毒性。因此，更有效的治疗选择 较低的毒性对于改善 CoCa 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 导致目前提供的化疗药物（5FU 和奥沙利铂）效果不佳的机制以及 开发更有效、毒性更小的治疗方法。拟议的调查基于我们发布的和 初步数据显示 (i) CoCa 细胞和组织中 CCR6 表达较高； (ii) CCR6 阳性表达 与疾病阶段相关； (iii) CCR6/CCL20具有生物活性并促进迁移和侵袭 CoCa，(iv) CCR6/CCL20 激活 β-连环蛋白、Snail、波形蛋白、α-SMA 并下调 E-钙粘蛋白，表明 该轴在维持已知对细胞反应不太敏感的间充质表型方面的重要性 化疗。基于此，我们假设 CCR6-CCL20 轴支持细胞和分子 重新编程以逃避化疗并开发针对 CCR6/CCL20 的疗法将改善 化疗疗效。将使用以下目标来检验该假设。目标 1：定义 CCR6- 与化疗反应不良相关的介导分子机制。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 癌细胞采取分子绕行来促进有助于忽略细胞毒性作用的细胞和分子表型 的传统化疗。此外，我们将确定阻断 CCR6/CCL20 轴是否会改善 次优剂量下 5-FU 和奥沙利铂的细胞毒性。此外，利用临床样本，我们将建立 CCR6/CCL20 对化疗反应的影响。目标 2：确定 CCR6 抑制对 体内化疗反应。使用异种移植和同基因小鼠模型，该目标将确定 CCR6/CCL20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 CCR6/CCL20 抑制对全身和肿瘤免疫的影响，无论有或没有 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变化 涉及改善化疗效果和器官毒性的机制。完成这个目标将 提供使用 CCR6/CCL20 定向治疗作为新治疗方式的基本原理。这个提议 研究是新颖的，因为 CCR6/CCL20 对细胞和分子重编程的影响导致贫困 5-FU 和奥沙利铂的反应未经体外和体内测试。从这项研究中获得的信息将 对于设计具有最小毒性的高效治疗组合具有重要意义。这预期 治疗选择将改善 CoCa 的临床结果和患者的生活质量。