Defining and characterizing microenvironmental drivers of disseminated tumor cell dormancy in brain

定义和表征脑中播散性肿瘤细胞休眠的微环境驱动因素

基本信息

批准号：
10037395
负责人：
Cyrus M Ghajar
金额：
$ 48.35万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-05 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10037395
关键词：
Ablation Address Agonist Agrin Astrocytes Autopsy Basement membrane Binding Blood Vessels Bone Marrow Brain Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast cancer metastasis Cancer Patient Cell Proliferation Clinical Clinical Data Cues Data Deposition Development Dystroglycan Early Diagnosis Enzymes Goals Human Individual Investigation Laminin Lesion Liver Lung Malignant Neoplasms Measures Mediating Metastatic breast cancer Metastatic malignant neoplasm to brain Mutation Neoplasm Metastasis Organ Outcome Measure Pathway interactions Patients Penetrance Phase Publishing Recording of previous events Resources Seeds Seminal Signal Transduction Signaling Molecule Site Soil Specimen Suppressor-Effector T-Lymphocytes Systemic Therapy Testing Therapeutic Time Transgenic Mice Transgenic Model Ursidae Family Woman Work Xenograft Model base bone glycosylation high dimensionality in vivo innovation intravital imaging knock-down malignant breast neoplasm metastasis prevention mouse model mutant neoplastic cell prevent prophylactic receptor

项目摘要

Project Summary Brain metastases arise later than metastases at other sites. Once they do, they are rapidly debilitating and lethal. The time it takes for brain metastases to emerge suggests that a dormancy phase is involved. This notion is supported by clinical and experimental data. Indeed, our own preliminary data show that breast cancer cells become dormant upon entering the brain, and that emerging from this state is the rate-limiting step of metastasis. These data indicate that targeting dormant disseminated tumor cells (DTCs) is a logical approach to brain metastasis prevention. However, despite a growing understanding of dormancy mechanisms in common metastatic sites like lung and bone marrow, a parallel understanding of how DTCs are driven into a dormant state in brain has not developed. The overarching goal of this proposal is to address this issue. We will formulate a basic framework for how the brain microenvironment drives DTCs into a dormant state, with support from clinical specimens, so that we can leverage this understanding for therapies that keep DTCs dormant indefinitely. Our recent investigations have revealed that dormant DTCs occupy the brain’s vascular niche, where perivascular astrocytes suppress their outgrowth. We suspect that astrocytic contributions to the parenchymal basement membrane are responsible for DTC suppression, and that these contributions converge on a common receptor: dystroglycan. Therefore, our hypotheses are that: (i) astrocytic basement membrane is a key driver of DTC dormancy, and (ii) dystroglycan function must remain intact for DTCs to interpret these signals. We will test these hypotheses through two specific aims: Aim 1. Determine whether astrocytic basement membrane promotes and sustains DTC dormancy. Aim 2. Elucidate the dystroglycan-mediated signaling axis that effects DTC quiescence in brain. We have brought every relevant resource to bear in order to address these aims. These resources span: (i) long-term intravital imaging to determine the fate of DTCs following ablation of DTC-associated astrocytes; (ii) transgenic mice to measure the outcome of ablating astrocyte derived basement membrane molecules on DTC fate; (iii) rare clinical specimens to establish whether astrocytes and astrocytic basement membrane are asso- ciated with dormant DTCs in humans; and (iv) a host of mutant, over- and under- expression constructs to solve how dystroglycan functions from the outside-in to drive DTC quiescence. The significance and innovation of this work lie in the identification of the first dormancy drivers in brain, ultimately to unravel dystroglycan-driven signaling that effects disseminated breast tumor cell quiescence. This work will set the stage for agonists of dystroglycan function that serve as prophylactics for brain metastasis prevention.

项目概要脑转移比其他部位的转移出现得晚，一旦发生，它们就会迅速衰弱并恶化。脑转移出现所需的时间表明存在休眠阶段。事实上，我们自己的初步数据表明，乳房。癌细胞在进入大脑后会进入休眠状态，从这种状态中出现是限速步骤这些数据表明，靶向休眠播散性肿瘤细胞（DTC）是合乎逻辑的。然而，尽管人们对休眠机制的了解不断加深。在常见的转移部位（如肺和骨髓）中，对 DTC 如何被驱动进入一个平行的理解大脑中的休眠状态尚未发展为休眠状态。该提案的首要目标是解决这个问题。将制定大脑微环境如何驱动 DTC 进入休眠状态的基本框架，其中临床标本的支持，以便我们可以利用这种理解来治疗保留 DTC 的疾病无限期地休眠。我们最近的研究表明，休眠的 DTC 占据了大脑的血管生态位，其中我们怀疑血管周围星形胶质细胞抑制其生长。基底膜负责 DTC 抑制，并且这些贡献集中在共同受体：肌营养不良聚糖因此，我们的假设是：（i）星形胶质细胞基底膜是一种。 DTC 休眠的关键驱动因素，并且 (ii) 肌营养不良聚糖功能必须保持完整，DTC 才能解释这些我们将通过两个具体目标来检验这些假设：目标 1. 确定星形胶质细胞基底膜是否促进和维持 DTC 休眠。目标 2. 阐明影响大脑中 DTC 静止的肌营养不良聚糖介导的信号轴。为了实现这些目标，我们利用了所有相关资源：(i)。长期活体成像以确定 DTC 相关星形胶质细胞消融后的命运 (ii) 转基因小鼠测量 DTC 上星形胶质细胞来源的基底膜分子消融的结果命运；（iii）罕见的临床标本以确定星形胶质细胞和星形胶质细胞基底膜是否相关与人类休眠 DTC 相关；以及 (iv) 一系列突变、过度表达和表达不足的构建体解决肌营养不良聚糖如何从外到内发挥作用以驱动 DTC 静止。这项工作的意义和创新在于识别了大脑中第一个休眠驱动因素，最终解开影响播散性乳腺肿瘤细胞静止的肌营养不良聚糖驱动的信号传导。这项工作将为肌营养不良聚糖功能激动剂奠定基础，作为脑转移的预防剂预防。