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

项目摘要 乳腺癌是第一个最常见的诊断癌症和第二个最常见的死亡原因的妇女 国际吧患有IV期乳腺癌的乳腺至脑转移（BBM）的患者预后不良， 神经变性，<10个月的生存期，并占所有乳腺癌相关死亡的10%。出现转移 原发性乳腺肿瘤的循环间充质型细胞在血液学扩散后在大脑中的作用。 能够适应独特的脑微环境或“土壤”的有能力的肿瘤细胞“种子”，然后将定殖， 建立转移性肿瘤。我们最近发现，BBM表现出神经元的特性，成为GABA能， 利用神经递质γ-氨基丁酸（GABA）作为致癌代谢物。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志物，表明这些肿瘤模拟了神经元的突触连接/可塑性。 神经元特性与大脑微环境的可能串扰。越来越多的证据表明， 脑微环境在转移性癌症的形成和发展中的重要性。脑脊髓 由脉络丛细胞（CP）产生的液体（CSF）沐浴脑和脊柱实质，类似于“流水 通过稻田”--从而作为一个最初的环境，使乳腺癌细胞循环到大脑的中央， 神经系统虽然血脑屏障（BBB）在乳腺-脑转移中的作用已被广泛研究， 研究，脉络丛，血-CSF屏障和CSF作为微环境生态位的贡献 大部分尚未被探索我们的初步数据表明，乳腺癌暴露于脉络膜/CSF 微环境导致上皮向间充质转化（EMT）的丧失和突触可塑性的诱导， BBM细胞。我们进一步表明，当BBM接种在CSF中时，脑屏障整体增加- 磁导率我们假设脉络膜/CSF微环境是定植的通道， 和乳腺-脑转移中突触可塑性的建立。使用患者衍生的独特优势 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：特异性目的1，作为一种 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;特异性目的 2，促进BBM中脑突触可塑性的诱导;和具体目标3，影响血液渗透性- 脑屏障和促进通过体循环的进一步转移。目前的建议将进一步阐明 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。 脑转移瘤患者的新型治疗干预。

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.