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: 10581506
• 负责人: Josh Neman-Ebrahim
• 金额: $ 45.89万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581506
• 关键词: Adhesions; Affect; Bathing; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Substitutes; Brain; Brain Neoplasms; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Carcinoma; Catabolism; Cause of Death; Cell Communication; Cells; Central Nervous System; Cerebrospinal Fluid; Cessation of life; Choroid; Choroid Plexus Neoplasms; Circulation; Coculture Techniques; Connexins; Corticotropin-Releasing Hormone Receptors; Data; Development; Diagnostic; Disease; Disseminated Malignant Neoplasm; Early Diagnosis; Electrical Resistance; Epithelium; Exhibits; Exposure to; Extracellular Matrix Proteins; Focal Adhesions; GAD67 enzyme; Gene Expression; Goals; Growth; Hematology; In Vitro; Injections; Integrins; Intercellular Junctions; Interleukin-13; Invaded; Isotopes; Knock-in; Knock-out; Lentivirus; Life; 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; Neurobiology; Neurons; Neurotransmitters; Non-Invasive Detection; Operative Surgical Procedures; Pathway interactions; Patients; Permeability; Phenotype; Production; Prognosis; Property; Protein Biosynthesis; Protein phosphatase; Proteins; Publishing; Research; Resected; Rice; Role; Running; Soil; Source; Spectrum Analysis; Spinal Injections; Structure of choroid plexus; Synapses; Synaptic plasticity; Therapeutic; Tight Junctions; Transgenic Mice; Tumor Cell Invasion; Valproic Acid; Vertebral column; Water; Woman; Work; Xenograft procedure; barrier to testing; blood cerebrospinal fluid barrier; blood-brain barrier crossing; 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; neural; neurodevelopment; novel; novel therapeutic intervention; overexpression; promoter; 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.

项目概要 乳腺癌是女性第一大最常诊断的癌症，也是女性第二大常见死亡原因 全世界。 IV 期乳腺癌发生乳至脑转移 (BBM) 的患者预后较差， 神经退行性变，生存期<10 个月，占所有乳腺癌相关死亡的 10%。出现转移 来自原发性乳腺肿瘤的循环间充质型细胞的血液学扩散后在大脑中。 有能力的肿瘤细胞“种子”，能够适应独特的大脑微环境或“土壤”，然后将殖民并发展 建立转移性肿瘤。我们最近表明，BBM 具有神经元特性，具有 GABA 能，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 与大脑微环境可能发生串扰的神经元特性。不断积累的证据凸显了 大脑微环境在转移性癌症的形成和进展中的重要性。脑脊髓 脉络丛细胞（CP）产生的液体（CSF）沐浴大脑和脊柱实质，类似于“水流” 穿过稻田”——因此作为循环乳腺癌细胞到达中枢的大脑的初始环境 神经系统。尽管血脑屏障（BBB）在乳至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贡献 很大程度上尚未被探索。我们的初步数据表明乳腺癌暴露于脉络膜/脑脊液 微环境导致上皮间质转化（EMT）丧失并诱导突触可塑性 BBM 细胞。我们进一步表明，当 BBM 植入脑脊液时，脑屏障的整体增加 - 渗透性。我们假设脉络膜/脑脊液微环境有助于作为定植的门户， 以及乳腺脑转移中突触可塑性的建立。利用源自患者的独特优势 手术切除的 BBM 异种移植物和 Reeler 转基因小鼠模型（通常用于研究突触可塑性） 神经发育），我们将研究 CP/CSF 肿瘤微环境的潜在作用：具体目标 1，作为 GABA 的非神经元来源，可用作 BBM 非侵入性早期检测的生物标志物；具体目标 2、促进BBM中大脑突触可塑性的诱导；和具体目标 3，影响血液的渗透性- 脑屏障并通过体循环促进进一步转移。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乳腺癌的发展开辟途径 针对脑转移患者的新型治疗干预措施。