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.

项目摘要/摘要 美国大约有40万人有骨转移，绝大多数发生在脊柱中。 脊柱转移导致骨折，疼痛，麻痹和巨大的医疗保健费用。这种病理 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肿瘤生长和柔软的进展中起着重要作用 组织疾病特别是髓样细胞。另外，骨髓内的免疫细胞组成 微环境可能因位置而有所不同，进一步有助于癌细胞的免疫逃生和可变 转移率。免疫微环境在骨髓和差分表达中的作用 尚未广泛研究不同骨骼中的髓样细胞的。我们已经初步检查了 不同骨区域的免疫微环境，观察到免疫细胞种群的差异 在脊柱和股骨之间。基于先前在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中的这些差异以收集 可以转化为限制或阻止转移到脊柱的靶向疗法的知识。我们 因此假设有一个免疫抑制签名，由髓样变化驱动 与长骨相比，椎体中的种群，在癌症的情况下，这种特征 增强了。我们的方法以飞行时间的形式利用高保真，高通量技术 光谱法（Cytof）和单细胞RNA-SEQ（SCRNA-SEQ）以全球询问细胞种群 特别异构背景的背景，以构建对致癌信号通路的见解 将免疫细胞与骨髓小裂内的肿瘤表型联系起来。为了检验我们的假设， 我们提出以下两个具体目的：1）表征本地和转移性前的差异 椎骨和长骨之间的免疫细胞景观。 2）确定功能意义 椎骨与长骨之间的免疫种群差异在肿瘤起始和 脊柱允许生长。申请人组建了一个高质量和特定的指导委员会 密歇根大学的专业可用。这个强大的指导委员会，培训环境， 研究建议将提供必要的资源，以成功完成该建议的项目。 该提案的结果将提高我们对骨转移和骨免疫学的理解以及 促进识别可用于改进的替代疗法的独特高度特定靶标 脊柱转移患者的临床结局。此外，该项目将为申请人培养一个新的 在骨气免疫学和转移性疾病的新兴领域中可以使用的技能。最终， 申请人将使用此奖项生成其他数据，以获得壁外资金并推进他的 职业是脊柱肿瘤学和骨气免疫学领域的外科医生科学家。