Microenvironmental contribution of the Choroid Plexus and Cerebral Spinal Fluid in breast to brain metastases

乳腺脉络丛和脑脊液微环境对脑转移的影响

• 批准号: 10334411
• 负责人: Josh Neman-Ebrahim
• 金额: $ 46.83万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-21 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334411
• 关键词: Affect; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Circulation; Blood Substitutes; Brain; Brain Neoplasms; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Carcinoma; Catabolism; Cause of Death; Cell Adhesion; Cells; Cerebrospinal Fluid; Cessation of life; Choroid; Choroid Plexus Neoplasms; Coculture Techniques; Connexins; Corticotropin-Releasing Hormone Receptors; Data; Development; Diagnostic; Disease; Disseminated Malignant Neoplasm; Early Diagnosis; Electrical Resistance; Epithelial; Exhibits; Exposure to; Extracellular Matrix Proteins; Focal Adhesions; GAD67 enzyme; Gene Expression; Goals; Growth; Hematology; In Vitro; Injections; Integrins; Intercellular Junctions; Interleukin-13; Isotopes; Knock-in; Knock-out; Lentivirus; Life; Light; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Mesenchymal; Metabolism; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Modeling; Molecular Analysis; Mutant Strains Mice; Neoplasm Metastasis; Nerve Degeneration; Neuraxis; Neurobiology; Neurons; Neurotransmitters; Non-Invasive Cancer Detection; Operative Surgical Procedures; Pathway interactions; Patients; Permeability; Phenotype; Production; Prognosis; Property; Protein Biosynthesis; Protein phosphatase; Proteins; Publishing; Research; Resected; Rice; Role; Running; Seeds; Soil; Source; Spectrum Analysis; Structure of choroid plexus; Synapses; Synaptic plasticity; Testing; Therapeutic; Tight Junctions; Transgenic Mice; Transitional Epithelium; Tumor Cell Invasion; Valproic Acid; Vertebral column; Water; Woman; Work; Xenograft procedure; blood cerebrospinal fluid barrier; blood-brain barrier permeabilization; brain parenchyma; cancer diagnosis; cell type; design; early detection biomarkers; epithelial to mesenchymal transition; experimental study; gamma-Aminobutyric Acid; in vivo; in vivo Model; innovation; insight; knock-down; lateral ventricle; malignant breast neoplasm; migration; mouse model; neoplastic cell; neurodevelopment; novel; novel therapeutic intervention; overexpression; promoter; relating to nervous system; response; targeted treatment; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY Breast cancer is the first most frequently diagnosed cancer and the second most common cause of death in women worldwide. Patients with breast-to-brain metastases (BBMs) from stage IV breast carcinoma have poor prognosis, neurological degeneration, <10-month survival, and account for 10% of all breast cancer related deaths. Metastases arise in the brain following hematological spread of circulating mesenchymal-type cells from primary breast tumors. Competent tumor cell “seeds”, which can adapt to the unique brain microenvironments or “soil”, will then colonize and establish metastatic tumors. We recently showed that BBMs exhibit neuronal properties, become GABAergic, and can utilize the neurotransmitter gamma-Aminobutyric acid (GABA) as an onco-metabolite. Our current results show that BBMs express neuron-specific markers of synaptic connectivity/plasticity, indicating that these tumors mimic the neuronal properties for possible cross-talk with the brain microenvironment. Accumulating evidence underlines the importance of the brain microenvironment in the establishment and progression of metastatic cancers. The cerebrospinal fluid (CSF) produced by choroid plexus cells (CP) bathes the brain and spine parenchyma, analogous to “water running through rice field” --and thus serves as an initial milieu to the brain for circulating breast cancer cells that reach the central nervous system. Although the role of the blood-brain-barrier (BBB) in breast-to-brain metastasis has been widely studied, the contribution of the choroid plexus, the blood-CSF-barrier, and the CSF as a microenvironmental niche has been largely unexplored. Our preliminary data suggest that breast cancer exposure to the choroid/CSF microenvironment results in loss of epithelial to mesenchymal transition (EMT) and induction of synaptic plasticity in BBM cells. We further show that when BBMs are seeded in the CSF, there is a global increase in the brain barrier- permeability. We hypothesize that the choroid/CSF microenvironment contributes as a gateway for colonization, and establishment of synaptic plasticity in breast-to-brain metastases. Using unique strengths of patient-derived surgically resected BBM xenografts and Reeler transgenic mouse model (normally used to study synaptic plasticity in neurodevelopment), we will investigate the potential roles of the CP/CSF tumor microenvironment: Specific Aim 1, as a non-neuronal source of GABA that can be used as a biomarker for non-invasively early detection of BBMs; Specific Aim 2, facilitating induction of brain synaptic plasticity in BBMs; and Specific Aim 3, in impacting permeability of the blood- brain-barrier and facilitating further metastasis through systemic circulation. The current proposal will shed further light on understanding how metastatic breast cancer cells adapt to their neural niche and open avenues for the development of novel therapeutic interventions for patients with brain metastases.

项目摘要 乳腺癌是第一个最常见的癌症，也是女性第二常见的死亡原因 全世界。 IV期乳腺癌的乳腺转移患者（BBM）的预后不良， 神经系统变性，<10个月的生存期，占所有与乳腺癌相关的死亡的10％。转移出现 在大脑中，来自原发性乳腺肿瘤的循环间充质型细胞的血液学扩散。 可以适应独特的脑微环境或“土壤”的主管肿瘤细胞“种子”，然后将定居并定居 建立转移性肿瘤。我们最近表明，BBM暴露了神经元特性，成为GABA能，并且可以 将神经递质伽马氨基丁酸（GABA）用作onco-亚赛代谢物。我们目前的结果表明 BBMS表达突触连通性/可塑性的神经元特异性标记，表明这些肿瘤模仿 神经元特性，可与脑微环境进行串扰。积累的证据强调 大脑微环境在转移性癌症的建立和发展中的重要性。大脑脊髓 脉络膜丛细胞（CP）产生的液体（CSF）BES脑和脊柱实质，类似于“水运行的水 通过稻田” - 因此，作为循环乳腺癌细胞到达中心的乳腺癌细胞的初始环境 神经系统。尽管血脑屏障（BBB）在乳腺转移中的作用已广泛 研究脉，脉络丛，血液-CSF弹药和CSF的贡献为微环境利基市场 在很大程度上是出乎意料的。我们的初步数据表明乳腺癌暴露于脉络膜/CSF 微环境导致上皮损失至间质转变（EMT），并诱导突触可塑性 BBM细胞。我们进一步表明，当BBM播种在CSF中时，脑屏障的全球增加 - 渗透性。我们假设脉络膜/CSF微环境成为定殖的门户， 并在乳腺转移酶中建立突触可塑性。利用患者衍生的独特优势 手术控制的BBM Xenographictics和Reeler转基因小鼠模型（通常用于研究合成可塑性 神经发育），我们将研究CP/CSF肿瘤微环境的潜在作用：特定目标1，作为A 非神经元来源，可以用作非侵入性早期检测的生物标志物；具体目标 2，促进BBM中脑合成可塑性的诱导；和特定的目标3，影响血液的渗透性 通过全身循环，大脑障碍并支持进一步的转移。当前的提议将进一步阐明 了解转移性乳腺癌细胞如何适应其神经元小众并开放途径 脑转移患者的新型热干预措施。