The role of differential bone marrow immune landscape in permissive tumor growth in the spine

差异性骨髓免疫景观在脊柱肿瘤生长中的作用

• 批准号: 10438095
• 负责人: Michael James Strong
• 金额: $ 0.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-01-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438095
• 关键词: Alternative Therapies; Animal Model; Award; Bone Marrow; Cancer Patient; Cells; Clinical; Data; Disease; Environment; Extramural Activities; Femur; Fostering; Fracture; Functional disorder; Funding; Future; Glean; Goals; Grant; Growth; Health Care Costs; Human; Immune; Immunology; Immunophenotyping; Implant; Knowledge; Lead; Link; Location; Longevity; Malignant Neoplasms; Mentorship; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Spine; Michigan; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Neurosurgeon; Oncogenic; Oncology; Pain; Paralysed; Pathologic Processes; Patient-Focused Outcomes; Patients; Phenotype; Play; Population; Prevalence; Research; Research Proposals; Resources; Role; Sampling; Scientist; Signal Pathway; Soft Tissue Disorder; Soft Tissue Neoplasms; Surgeon; Testing; Training; Translating; Tumor Escape; Universities; Vertebral column; base; bone; cancer cell; career; cell type; differential expression; high throughput technology; improved; in vitro Assay; insight; long bone; medical specialties; mortality; mouse model; new therapeutic target; novel; osteoimmunology; prevent; single-cell RNA sequencing; spine bone structure; success; targeted treatment; tibia; time of flight mass spectrometry; tumor; tumor growth; tumor initiation; tumor progression; tumor-immune system interactions; vertebra body

PROJECT SUMMARY/ABSTRACT Roughly 400,000 people in the U.S. have bone metastases, the vast majority occurring in the spine. Metastases to the spine results in fractures, pain, paralysis, and enormous health care costs. This pathological process is not fully understood. Immune cells are an important constituent of the bone marrow microenvironment and have been shown to play a significant role in tumor growth and progression in soft tissue disease specifically myeloid cells. Additionally, immune cell composition within the bone marrow microenvironment may vary by location, further contributing to immune escape of cancer cells and variable rates of metastases. The role of the immune microenvironment in bone marrow and the differential expression of myeloid cells in different bones has not been extensively investigated. We have preliminarily examined the immune microenvironments in different bone regions and observed differences in the immune cell populations between the spine and the femur. Based on previous research in soft tissue tumor progression and our novel preliminary data, we will further investigate these differences in local bone immune environments to glean knowledge that can be translated into targeted therapies that limit or prevent metastases to the spine. We therefore hypothesize that there is an immunosuppressive signature, driven by changes in the myeloid population, in the vertebral bodies compared to the long bones and that in the setting of cancer, this signature is enhanced. Our approach utilizes high-fidelity, high-throughput technology in the form of time-of-flight mass spectrometry (CyTOF) and single-cell RNA-seq (scRNA-seq) to globally interrogate cell populations in the context of a particularly heterogeneous background to construct insights into the oncogenic signaling pathways linking immune cells to the tumor-promoting phenotype within the bone marrow niche. To test our hypothesis, we propose the following two specific aims: 1) Characterize the differences in the native and premetastatic immune cell landscapes between the vertebrae and long bone. 2) Determine the functional significance of immune population differences between vertebrae and long bones on tumor initiation and permissive growth to spine. The applicant assembled a mentorship committee of high quality and specific specialties available at the University of Michigan. This strong mentorship committee, training environment, and research proposal will provide the necessary resources to successfully complete this proposed project. Results from this proposal will advance our understanding of bone metastases and bone immunology and facilitate the identification of unique highly specific targets that may be used in alternative therapies to improve clinical outcomes for patients with spine metastases. Additionally, this project will foster for the applicant a new skillset that can be used in this emerging field of osteoimmunology and metastatic disease. Ultimately, the applicant will use this award to generate additional data for obtaining extramural funding and advancing his career as a surgeon scientist in the field of spine oncology and osteoimmunology.

项目概要/摘要 美国大约有 40 万人患有骨转移，其中绝大多数发生在脊柱。 脊柱转移会导致骨折、疼痛、瘫痪和巨大的医疗费用。这种病态的 过程尚未完全理解。免疫细胞是骨髓的重要组成部分 微环境并已被证明在软组织中的肿瘤生长和进展中发挥重要作用 组织疾病，特别是骨髓细胞。此外，骨髓内的免疫细胞组成 微环境可能因地点而异，进一步促进癌细胞的免疫逃逸，并且变量 转移率。骨髓免疫微环境的作用及其差异表达 不同骨骼中骨髓细胞的作用尚未得到广泛研究。我们已经初步审查了 不同骨区域的免疫微环境并观察到免疫细胞群的差异 脊柱和股骨之间。基于之前对软组织肿瘤进展的研究和我们的新颖 初步数据，我们将进一步研究局部骨免疫环境的这些差异，以收集 这些知识可以转化为限制或预防脊柱转移的靶向治疗。我们 因此假设存在由骨髓细胞变化驱动的免疫抑制特征 与长骨相比，在椎体中以及在癌症的情况下，这个特征 得到增强。我们的方法利用飞行时间质量形式的高保真度、高通量技术 光谱分析 (CyTOF) 和单细胞 RNA 测序 (scRNA-seq) 来全面询问细胞群 在特别异质的背景下构建对致癌信号通路的见解 将免疫细胞与骨髓生态位内的肿瘤促进表型联系起来。为了检验我们的假设， 我们提出以下两个具体目标：1）表征天然和转移前的差异 椎骨和长骨之间的免疫细胞景观。 2）确定功能意义 椎骨和长骨之间的免疫群体差异对肿瘤发生和 允许脊柱生长。申请人组建了一个高素质、专业的导师委员会 密歇根大学提供的专业。这个强大的导师委员会、培训环境， 研究提案将为成功完成该拟议项目提供必要的资源。 该提案的结果将增进我们对骨转移和骨免疫学的理解， 促进独特的高度特异性靶标的识别，这些靶标可用于替代疗法以改善 脊柱转移瘤患者的临床结果。此外，该项目将为申请人培养一个新的 可用于骨免疫学和转移性疾病这一新兴领域的技能。最终， 申请人将利用该奖项来生成额外的数据，以获取校外资金并推进他的发展 作为脊柱肿瘤学和骨免疫学领域的外科医生科学家。