Targeting Chemotherapy-induced Breast Cancer Stemness

项目总结/摘要 术前或新辅助治疗（NT）越来越多地用于局部晚期或 炎症性乳腺癌（BC），以允许最佳手术。虽然病理完全缓解， 与生存率增加相关，许多患者没有反应和/或发生致命的转移性疾病 NT之后。我们的初步数据表明，化疗诱导单核细胞趋化因子的血液水平， 蛋白质（MCP），其可以刺激癌症干细胞样细胞（CSC）表型以促进肿瘤恶性。 本研究的目的是剖析NT方案诱导CSC的机制 乳腺肿瘤中的表型。我们将研究MCP介导的系统机制和局部机制。 癌症分泌的miRNAs介导的机制，并将测试阻断这些事件的干预策略 在化疗期间。总体目标是设计干预措施，最大限度地发挥 通过防止NT诱导的CSC扩增进行抗癌治疗。在目标1中，我们将首先使用人类和 小鼠BC细胞，以确定MCP如何激活受体导致Numb降解和Notch 激活以促进CSC。将鉴定介导MCP对癌细胞作用的其他效应物。 小鼠肿瘤模型将用于确定MCP对肿瘤中非癌细胞的影响 微环境，其可以反过来调节细胞因子环境以影响CSC。在目标2中，我们 确定在我们的初步研究中鉴定的化疗诱导的miRNAs是否协同刺激 具有全身性MCP升高的CSC。在目标3中，患者来源的异种移植物肿瘤模型和小鼠肿瘤移植物肿瘤模型均为非特异性的。 模型将用于确定靶向本文鉴定的抗CSC的各种药剂的抗CSC作用。 途径。然后，我们将确定NT是否诱导BC患者的单核细胞扩增，以及MCP启动的 信号传导与原代人BC中的CSC频率相关。拟议工作的结果将 为将来使用先前使用的CCR 2抑制剂之一进行临床试验提供机制和临床前基础 针对非癌症疾病开发，以靶向BC患者中治疗诱导的CSC。改善我们 理解NT后造血细胞、大量癌细胞和CSC群体之间的相互作用 将允许开发改进的组合疗法以减少治疗抗性和肿瘤 复发它还可以提供对根据需要定制的治疗方案的临床应用的洞察， 个体患者，最终导致抗癌治疗的成功率增加。

PROJECT SUMMARY/ABSTRACT Preoperative or neoadjuvant therapy (NT) is increasingly used in patients with locally advanced or inflammatory breast cancer (BC) to allow optimal surgery. Although a pathologic complete response has been associated with increased survival, many patients do not respond and/or develop lethal metastatic disease after NT. Our preliminary data indicate that chemotherapy induces blood levels of monocyte chemoattractant proteins (MCPs), which can stimulate the cancer stem-like cell (CSC) phenotype to promote tumor malignancy. The goal of this study is to dissect the mechanisms through which NT regimens induce the CSC phenotype in breast tumors. We will investigate both a MCP-mediated systemic mechanism and a local mechanism mediated by cancer-secreted miRNAs, and will test intervention strategies that block these events during chemotherapy. The overall goal is to design interventions that maximize the beneficial effects of anticancer treatment by preventing NT-induced CSC expansion. In Aim 1, we will first use human and mouse BC cells to determine how receptor activation by MCPs leads to Numb degradation and Notch activation to promote CSCs. Additional effectors mediating MCPs' effect on cancer cells will be identified. Mouse tumor models will be used to determine the effect of MCPs on non-cancer cells in the tumor microenvironment, which may in turn regulate the cytokine environment to influence CSCs. In Aim 2, we will determine if the chemotherapy-induced miRNAs identified in our preliminary study synergistically stimulate CSCs with systemically elevated MCPs. In Aim 3, patient-derived xenograft tumor models and mouse tumor models will be used to determine the anti-CSC effects of various agents targeting the herein identified pathways. We will then determine if NT induces monocyte expansion in BC patients and if MCP-initiated signaling is associated with CSC frequency in primary human BCs. Results from the proposed work will provide a mechanistic and pre-clinical basis for a future clinical trial using one of the CCR2 inhibitors previously developed for non-cancer diseases to target treatment-induced CSCs in BC patients. Improving our understanding of the interplay between hematopoietic cells, bulk cancer cells, and CSC populations after NT will allow the development of improved combinatorial therapies to reduce therapeutic resistance and tumor relapse. It may also provide insight into the clinical application of therapeutic regimens tailored to the need of individual patients, ultimately leading to an increased success of anticancer treatment.