Mechanisms of neuroinflammation in brain metastasis progression

神经炎症在脑转移进展中的机制

• 批准号: 10642124
• 负责人: Siyuan Zhang
• 金额: $ 38.31万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10642124
• 关键词: Adjuvant Therapy; Algorithmic Analysis; Antineoplastic Agents; Architecture; Basic Science; Behavior; Blood - brain barrier anatomy; Bone Marrow; Brain; Brain Neoplasms; Cancer Survivor; Cells; Clinic; Clinical; Clinical Treatment; Coupled; Data; Development; Diagnosis; Fright; Future; Genetic; Genetic Variation; Genomic approach; Genotype; Global Change; Goals; Heterogeneity; ITGAM gene; Image Analysis; Immune; Immune system; In Situ; Incidence; Inflammatory; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Metastatic malignant neoplasm to brain; Microglia; Modeling; Molecular; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Neurodegenerative Disorders; Organ; Patients; Pattern; Phenotype; Plant Roots; Primary Neoplasm; Relapse; Research; Resolution; Role; Sampling; Screening for cancer; Site; Statistical Models; Therapeutic; Tissue Sample; Tissue imaging; Tissues; Transgenic Mice; Treatment Protocols; Validation; base; brain tissue; cell type; clinical practice; imaging approach; imaging modality; improved; innovation; insight; interdisciplinary approach; macrophage; malignant breast neoplasm; metastasis prevention; mortality; mouse model; multidisciplinary; neoplastic cell; neuroinflammation; new therapeutic target; novel; pre-clinical; pre-clinical research; preclinical efficacy; rational design; receptor; single-cell RNA sequencing; spatiotemporal; success; targeted treatment; trait; transcriptome; tumor progression

Project Summary Title: Mechanisms of neuroinflammation in brain metastasis progression Despite significant progress in early cancer screening and treatment regimens for primary tumors, the overall mortality of patients with metastatic relapse has not improved in the past two decades. Many sites of metastatic relapse are commonly diagnosed in the clinic, but brain metastasis is the most devastating with a median survival of fewer than six months. Thriving in a "sanctuary" protected by the blood-brain barrier (BBB), brain metastases are shielded from most anti-cancer drugs. As a result, the incidence of brain metastasis is increasing, despite increasing control of primary tumors. Thus, to reduce cancer mortality, rationally designed therapeutics, based on a mechanistic understanding of metastasis in the context of the unique brain microenvironment, are urgently needed for brain metastasis patients. The immune system has indisputable and ubiquitous roles in regulating both primary tumors and metastases. Traditionally viewed as immunoprivileged organ, the role of neuroinflammation in brain tumor progression is largely underexplored. In this proposed study, we will use transgenic mouse models and state-of-the-art genomics and imaging approach to trace and analyze the role of highly heterogeneous cell types involved in neuroinflammation and their roles in regulating brain metastatic outgrowth. This collaborative effort from a multidisciplinary team, including a cancer biologist, an expert in neuroinflammation, a computational biologist and a bioinformatician and will allow us to: 1) dissect distinct contribution subpopulation of myeloid cells in regulating brain metastasis at phenotypical level (Aim 1); 2) visualize and quantitatively measure the behavior of brain microenvironmental niche and transcriptome heterogeneity of inflammatory myeloid cell that that nurtures metastasis in brain (Aim 2). 3) Targeting pro-inflammatory myeloid cells as means of brain metastasis prevention. Shifting the current clinical treatment model relies on new in-depth mechanistic insights obtained through basic and pre-clinical innovative research. Utilizing cutting-edge sequencing and imaging modality coupled with classic transgenetic models and clinical tissue samples, we now have the unprecedented capacity to systematically dissect the traits of metastatic behavior and discover potential novel therapeutic targets for paradigm-shifting novel adjuvant therapy for brain metastasis patients.

项目摘要 标题：脑转移进展中的神经炎症机制 尽管在原发性肿瘤的早期癌症筛查和治疗方案方面取得了重大进展， 在过去二十年中，转移性复发患者的总体死亡率没有改善。许多网站 转移性复发是临床上常见的诊断，但脑转移是最具破坏性的， 中位生存期不到6个月。在受血脑屏障（BBB）保护的“避难所”中茁壮成长， 大多数抗癌药物都无法治疗脑转移瘤。因此，脑转移的发病率是 尽管原发性肿瘤的控制增加，但仍在增加。因此，要降低癌症死亡率， 治疗学，基于在独特的大脑背景下对转移的机械理解， 微环境，是脑转移患者迫切需要的。免疫系统有着无可争议的 并且在调节原发肿瘤和转移中普遍存在的作用。传统上被视为 尽管神经炎症是免疫特异性器官，但神经炎症在脑肿瘤进展中的作用在很大程度上未被探索。在 在这项研究中，我们将使用转基因小鼠模型和最先进的基因组学和成像技术， 追踪和分析参与神经炎症的高度异质性细胞类型的作用的方法， 它们在调节脑转移瘤生长中的作用。这是一个多学科团队的合作努力， 包括癌症生物学家、神经炎症专家、计算生物学家和生物信息学家 并将使我们能够：1）解剖髓样细胞在调节脑转移中的不同贡献亚群 在表型水平（目标1）; 2）可视化和定量测量脑微环境的行为 炎症性髓样细胞巢和转录组异质性促进脑转移（目 2）的情况。3)靶向促炎性骨髓细胞作为预防脑转移的手段。改变电流 临床治疗模式依赖于通过基础和临床前研究获得的新的深入机制见解， 创新研究。利用先进的测序和成像模式，结合经典的转基因技术， 模型和临床组织样本，我们现在有前所未有的能力，系统地解剖 转移行为的特点，并发现潜在的新的治疗靶点， 脑转移患者的辅助治疗。

项目成果

Multi-modal Single-Cell Analysis Reveals Brain Immune Landscape Plasticity during Aging and Gut Microbiota Dysbiosis.

• DOI: 10.1016/j.celrep.2020.108438
• 发表时间: 2020-12-01
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Golomb SM;Guldner IH;Zhao A;Wang Q;Palakurthi B;Aleksandrovic EA;Lopez JA;Lee SW;Yang K;Zhang S
• 通讯作者: Zhang S

Generating intravital super-resolution movies with conventional microscopy reveals actin dynamics that construct pioneer axons

用传统显微镜生成活体超分辨率电影揭示了构建先锋轴突的肌动蛋白动力学

• DOI: 10.1242/dev.171512
• 发表时间: 2019
• 期刊: Development
• 影响因子: 4.6
• 作者: Zhang, Yide;Nichols, Evan L.;Zellmer, Abigail M.;Guldner, Ian H.;Kankel, Cody;Zhang, Siyuan;Howard, Scott S.;Smith, Cody J.
• 通讯作者: Smith, Cody J.

Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer.

含有死亡效应结构域的蛋白质诱导三阴性乳腺癌细胞周期抑制的脆弱性。

• DOI: 10.1038/s41467-019-10743-7
• 发表时间: 2019
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Ni,Yingjia;Schmidt,KeonR;Werner,BarnesA;Koenig,JennaK;Guldner,IanH;Schnepp,PatriciaM;Tan,Xuejuan;Jiang,Lan;Host,Misha;Sun,Longhua;Howe,ErinN;Wu,Junmin;Littlepage,LaurieE;Nakshatri,Harikrishna;Zhang,Siyuan
• 通讯作者: Zhang,Siyuan

CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10.

• DOI: 10.1016/j.cell.2020.09.064
• 发表时间: 2020-11-25
• 期刊: Cell
• 影响因子: 64.5
• 作者: Guldner IH;Wang Q;Yang L;Golomb SM;Zhao Z;Lopez JA;Brunory A;Howe EN;Zhang Y;Palakurthi B;Barron M;Gao H;Xuei X;Liu Y;Li J;Chen DZ;Landreth GE;Zhang S
• 通讯作者: Zhang S