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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：
10158461
负责人：
Cyrus M Ghajar
金额：
$ 32.33万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10158461
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.

项目总结