Center for Systems-level Study of Metastasis

转移系统级研究中心

• 批准号: 10493336
• 负责人: Sohail F. Tavazoie
• 金额: $ 164.53万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493336
• 关键词: Automobile Driving; Bioinformatics; Biological; Biology; Breast Cancer Cell; Cell physiology; Cells; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Colorectal Cancer; Colorectal Neoplasms; Complex; Computer Analysis; Computing Methodologies; Development; Disease; Dissection; Endothelial Cells; Epidemiology; Event; Gene Expression; Generations; Genes; Genetic; Goals; Grant; Image; Immune; Immunity; Knowledge; Lymphatic; Malignant Neoplasms; Mammary Neoplasms; Medical Oncology; Memorial Sloan-Kettering Cancer Center; Metabolic; Methods; Molecular; Neoplasm Metastasis; Nervous system structure; Neuroepithelial; Neuroimmune; Neurons; Nutrient; Pathologic; Phase; Phenotype; Physicians; Positioning Attribute; Primary Neoplasm; Process; Property; RNA-Binding Proteins; Research Personnel; Role; Scientist; Series; Shapes; Signal Transduction; Signaling Protein; Site; System; Systems Biology; Technical Expertise; analytical method; biological systems; cancer cell; cancer therapy; cell type; chemotherapy; colorectal cancer metastasis; experience; innovation; insight; lymphatic vasculature; malignant breast neoplasm; multidisciplinary; nerve supply; neurotransmission; novel; prevent; programs; relating to nervous system; response; single cell sequencing; success; therapeutic target; tool; transcription factor; treatment response; tumor; tumor immunology; tumor metabolism; tumor progression

Project Summary: Metastatic disease is a complex, dynamic and emergent process that requires collective and coordinated interactions between many cell types, metabolites and the host. There is substantial clinico- pathologic and experimental evidence for critical roles of neural innervation, lymphatic interactions, metabolites and endothelial cells in regulating metastatic progression by altering cancer and immune cell functions. As such, these cellular interactions likely shape metastatic progression, responses to therapy and metastatic dissemination. However, we have a limited understanding of how these components coordinately regulate metastatic progression. This application describes a series of highly innovative multidisciplinary molecular, cell- biological, metabolic, massively-parallel single-cell sequencing and organismal methods applied towards defining the dynamic and emergent mechanisms by which neural cells, lymphatics, immune cells and metabolites interact to coordinately regulate metastatic progression—contributing to a systems-level understanding of metastasis. We aim to (i) define the role of neural innervation on metastatic progression by characterizing neuro- tumor and neuro-immune interactions and identifying neural signals and their pro-metastatic mechanisms of action, (ii) determine how endothelial cells regulate innervation of metastatic tumors, (iii) define the role of regionalized lymphatic interactions in driving metastatic progression and anti-metastatic immunity, (iv) assess the role of neuro-immune and neuro-epithelial interactions on early metastatic dissemination and colonization, (v) identify metabolite and protein signals that drive metastatic colonization, (vi) discover tumoral transcription factors and RNA-binding proteins that act downstream of neural and metabolic signals to drive emergent pro- metastatic gene expression programs, and (vii) determine the impact of standard chemotherapy on these diverse cellular interactions and metabolic determinants of metastatic progression. Our proposed MetNet Center will enhance our understanding of how interactions and crosstalk between cancer cells with nervous system cells, lymphatics, vasculature and immune cells enables emergence of metastatic disease. We will also assess how therapy impacts specific cell-cell and metabolic interactions of metastatic cells and provide insights into the impact of specific cellular interactions in the primary microenvironment on metastatic dissemination, including early dissemination. These findings will generate an integrated, systems-level understanding of metastasis, enabling development of a new generation of anti-cancer therapies that prevent critical emergent coordinated pro-metastatic interactions.

项目总结：转移性疾病是一个复杂的、动态的和紧急的过程，需要集体和有效的治疗