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Investigate and inhibit microglia support of brain metastases

研究并抑制小胶质细胞对脑转移的支持

基本信息

批准号：
10272360
负责人：
Melanie Hayden Gephart
金额：
$ 35.17万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10272360
关键词：
3-Dimensional Affect Air Animal Model Anti-CD47 Antigen Presentation Architecture Biological Assay Blood Circulation Bone Marrow Transplantation Brain Brain Neoplasms Busulfan CD47 gene CRISPR library CSF1 gene Cell Communication Cell Death Cells Cerebrospinal Fluid Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complex Custom Data Disease Progression Disseminated Malignant Neoplasm Distant Epithelial Evaluation Exhibits Extracellular Matrix Generations Genes Growth Human Immune Immunologic Surveillance Immunological Models Immunotherapy Inflammatory Inflammatory Response Interleukin-6 Interruption Intrinsic factor Knock-out Knowledge Ligands Liquid substance Macrophage Activation Malignant Neoplasms Measures Mediating Messenger RNA Metalloproteases Metastatic malignant neoplasm to brain Methods Microglia Modeling Monitor Mus Myeloid Cells Neoplasm Metastasis Neuroimmune Neurologic Organoids PTPNS1 gene Phagocytosis Phenotype Population Positioning Attribute Primary Neoplasm Production Prognosis Property Protocols documentation Publishing RNA analysis Recurrence Resistance Role Sampling Signal Transduction T-Cell Activation T-Lymphocyte Technology Testing Therapeutic Tumor Cell Invasion Tumor Immunity Tumor-associated macrophages Tumor-infiltrating immune cells aggressive therapy base cancer cell cytokine human disease implantation in vitro Model innovation macrophage migration mortality multidisciplinary neoplastic cell neuropathology novel novel strategies receptor single-cell RNA sequencing small molecule transcriptome tumor tumor microenvironment tumor progression tumor-immune system interactions weapons

项目摘要

1 ABSTRACT – PROJECT 2 2 Brain metastases are highly aggressive, treatment resistant malignancies with debilitating neurological sequelae 3 and a grave prognosis. Efforts to understand and modulate the metastatic brain tumor microenvironment (TME) 4 have great therapeutic potential. Studies have suggested that polarization of macrophages (M1 or M2) may be 5 helpful or harmful in cancer progression (1, 2). Microglia, the brain’s myeloid cells, function in immune 6 surveillance and mediate the tumor-related inflammatory response, including within the context of the metastatic 7 brain tumor microniche (tumor-associated macrophages and tumor-associated microglia). We hypothesize 8 brain metastases are supported in part by native microglia (3), and that these interactions can be 9 manipulated for therapeutic benefit. The role of microglia in brain metastases has been difficult to investigate 10 given the relative inaccessibility of brain metastases samples, inability to isolate human tumor-associated 11 microglia or monitor their interactions within the TME, and lack of models that include or allow manipulation of 12 microglia while still reliably recapitulating the human disease. To overcome these critical hurdles, we employ the 13 following innovative methods: (i) single cell RNA-sequencing (scRNA-seq) on fresh, human brain metastases 14 and normal surrounding brain (Neuropathology Core)(4, 5); (ii) isolation and dynamic array sequencing of cell 15 free messenger RNA (cfRNA) from human cerebrospinal fluid (6, 7); (iii) generation of human and murine-derived 16 brain metastasis 3D air-liquid interface (ALI) organoids that include tumor-associated microglia/macrophages 17 (Toolkit Core); and (iv) repopulation of microglia with circulation derived microglia-like cells (CDMCs) with 18 greater than 90% efficiency throughout the entire brain. These four innovative methods allow us to investigate 19 the role of tumor-associated microglia in human brain metastases, model immune cell interactions, and 20 manipulate their function in an animal model of metastatic malignancy. Our multidisciplinary team is uniquely 21 positioned to test the following three aims: (1) Test the extent to which tumor-associated microglia create an 22 immunosuppressive TME supporting brain metastasis. In addition to relating microglia function to brain 23 metastasis local recurrence and distant progression, we will cross-reference our findings with cancer cell intrinsic 24 factors (Project 1) and systemic macrophage reactivity (Project 3); (2) Model tumor-associated microglia within 25 the brain metastatic TME using ALI organoids. We will model tumor and tumor-associated microglia/macrophage 26 interactions and determine the impact of immunotherapy on microglia/macrophage activation and phagocytosis, 27 T-cell activation states, and cell death. Our findings will be integrated with expanding knowledge of cell-intrinsic 28 factors (Project 1) and brain-periphery immune interactions (Project 3); (3): Determine how high efficiency 29 microglia replacement with CDMCs inhibits brain metastasis. We will replace microglia with “weaponized” 30 CDMCs to inhibit cancer cell implantation and disease progression. 31

1摘要-项目2