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: 10091411
• 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/10091411
• 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; Cultured Cells; 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.

项目总结 乳腺癌是女性最常被诊断的癌症，也是女性第二常见的死亡原因。 全世界。IV期乳腺癌乳房脑转移患者预后较差， 神经退行性变，存活10个月，占所有乳腺癌相关死亡人数的10%。转移瘤出现 在原发乳腺肿瘤的循环间充质细胞血液学扩散后的脑组织中。 有能力的肿瘤细胞“种子”，可以适应独特的脑微环境或“土壤”，然后定植和 建立转移性肿瘤。我们最近表明，骨髓基质细胞具有神经元特性，可以成为GABA能细胞，并且可以 利用神经递质γ-氨基丁酸(GABA)作为肿瘤代谢物。我们目前的结果表明， BBM表达突触连接/可塑性的神经元特异性标记，表明这些肿瘤模仿 可能与大脑微环境产生串扰的神经元特性。越来越多的证据突显出 脑微环境在转移性癌症发生和发展中的重要性。脑脊液 脉络丛细胞(CP)产生的液体(CSF)沐浴在大脑和脊柱实质中，类似于“流水” 通过稻田“--从而为循环的乳腺癌细胞到达中央的大脑提供了初始环境 神经系统。尽管血脑屏障(BBB)在乳腺-脑转移中的作用已被广泛研究 研究了脉络丛、血-脑脊液屏障和脑脊液作为微环境生态位的作用 在很大程度上是未被开发的。我们的初步数据表明，乳腺癌暴露在脉络膜/脑脊液中 微环境导致大鼠上皮细胞向间充质转化的丧失和突触可塑性的诱导 BBM细胞。我们进一步表明，当骨髓间充质干细胞植入脑脊液时，脑屏障会出现全局性增加- 渗透性。我们假设脉络膜/脑脊液微环境作为殖民的门户， 以及在乳房到脑转移瘤中建立突触可塑性。使用患者派生的独特优势 手术切除的BBM异种移植和Reeler转基因小鼠模型(通常用于研究 )，我们将研究CP/CSF肿瘤微环境的潜在作用：特定目标1，作为一种 GABA的非神经性来源，可用作非侵入性早期检测BBMS的生物标志物；特定目的 2，促进骨髓间充质干细胞脑突触可塑性的诱导；以及特定目标3，在影响血液通透性方面- 脑屏障，并促进通过体循环进一步转移。目前的提案将进一步阐明 了解转移性乳腺癌细胞如何适应其神经生态位并为其发展开辟途径 脑转移瘤患者的新治疗干预措施。