Targeting Chemotherapy-induced Breast Cancer Stemness

项目摘要/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)使手术成为最佳选择。尽管病理上的完全应答已经 随着存活率的提高，许多患者没有反应和/或发生致命的转移性疾病。 在NT之后。我们的初步数据表明，化疗会诱导血液中单核细胞趋化物质的水平 蛋白质(MCPs)，可以刺激肿瘤干细胞(CSC)表型，促进肿瘤恶性转化。 本研究的目的是剖析NT方案诱导CSC的机制 乳腺肿瘤的表型。我们将研究MCP介导的系统机制和局部 由癌症分泌的miRNAs介导的机制，并将测试阻止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 防止NT诱导的CSC扩张的抗癌治疗。在目标1中，我们将首先使用人类和 小鼠BC细胞确定MCPs激活受体如何导致Numb降解和Notch 激活以促进CSC。将确定更多介导MCPs对癌细胞影响的效应器。 将使用小鼠肿瘤模型来确定MCPs对肿瘤中非肿瘤细胞的影响 微环境，这可能反过来调节细胞因子环境来影响CSCs。在目标2中，我们将 确定我们初步研究中发现的化疗诱导的miRNAs是否协同刺激 具有系统升高的MCP的CSC。在AIM 3中，患者来源的异种移植瘤模型和小鼠肿瘤 模型将被用来确定针对本文确定的目标的各种药物的抗CSC效果 小路。然后，我们将确定NT是否诱导BC患者单核细胞的扩张，以及MCP是否启动 在原始人的BCS中，信号与CSC的频率有关。拟议工作的成果将 为未来使用CCR2抑制剂之一的临床试验提供机制和临床前基础 为非癌症疾病开发，以靶向治疗诱导的BC患者的CSCs。改善我们的 了解移植后造血细胞、实体癌细胞和CSC群体之间的相互作用 将允许开发改进的组合疗法，以减少治疗阻力和肿瘤 旧病复发。它还可以为临床应用量身定做的治疗方案提供洞察力 患者个体，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.