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

• 批准号: 10601281
• 负责人: Cyrus M Ghajar
• 金额: $ 16.16万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 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/10601281
• 关键词: Defining; characterizing; microenvironmental; drivers; disseminated

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.

项目摘要 脑转移比其他部位的转移出现得晚。一旦他们这样做，他们迅速衰弱， 致命的脑转移瘤出现所需的时间表明它涉及到一个休眠阶段。这 这一观点得到了临床和实验数据的支持。事实上，我们自己的初步数据显示， 癌细胞进入大脑后进入休眠状态，从这种状态中出现是限速步骤 转移。这些数据表明，靶向休眠的播散性肿瘤细胞（DTC）是一种合乎逻辑的治疗方法。 预防脑转移的方法。然而，尽管对休眠机制的了解越来越多， 在常见的转移部位，如肺和骨髓，一个平行的理解DTC是如何驱动到一个 大脑中的休眠状态尚未发展。本提案的总体目标是解决这一问题。我们 将为大脑微环境如何驱动DTC进入休眠状态制定一个基本框架， 从临床标本的支持，使我们可以利用这种理解的治疗，保持DTC 无限期休眠 我们最近的研究表明，休眠的DTC占据了大脑的血管生态位， 血管周围的星形胶质细胞抑制它们的生长。我们怀疑星形胶质细胞对脑实质的贡献 基底膜负责DTC抑制，并且这些贡献集中在一个特定的区域。 共同受体：肌营养不良蛋白聚糖。因此，我们的假设是：（i）星形胶质细胞基底膜是一个 DTC休眠的关键驱动因素，以及（ii）肌营养不良蛋白聚糖功能必须保持完整，以便DTC解释这些 信号.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.阐明肌营养不良蛋白聚糖介导的影响DTC在脑内静止的信号轴。 为了实现这些目标，我们动用了一切有关资源。这些资源包括： 长期活体成像，以确定DTC相关星形胶质细胞消融后DTC的命运;（ii） 转基因小鼠，以测量在DTC上消融星形胶质细胞衍生的基底膜分子的结果 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是阿索- 与人类中的休眠DTC相关;和（iv）许多突变的、过表达和表达不足的构建体， 解决了肌营养不良蛋白聚糖如何从外向内发挥作用以驱动DTC静止。 本研究的意义和创新在于首次发现了脑内的休眠驱动因子， 最终解开肌营养不良聚糖驱动的信号传导，影响扩散的乳腺肿瘤细胞静止。这 这项工作将为肌营养不良蛋白聚糖功能的激动剂奠定基础， 预防