Center for Systems-level Study of Metastasis

转移系统级研究中心

• 批准号: 10271735
• 负责人: Sohail F. Tavazoie
• 金额: $ 169.63万
• 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/10271735
• 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; 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.

项目概述：转移性疾病是一个复杂、动态和紧急的过程，需要集体和 协调许多细胞类型、代谢物和宿主之间的相互作用。有大量的临床- 神经支配、淋巴相互作用、代谢物的关键作用的病理和实验证据 和内皮细胞通过改变癌症和免疫细胞功能来调节转移进展。因此，在本发明的一个方面， 这些细胞相互作用可能影响转移进展、对治疗的反应和转移 传播。然而，我们对这些组件如何协调调节的理解有限 转移性进展本申请描述了一系列高度创新的多学科分子，细胞- 生物、代谢、平行单细胞测序和生物体方法， 定义了神经细胞、代谢物、免疫细胞和代谢物 相互作用以协调调节转移进展-有助于系统水平理解 转移我们的目的是（i）通过表征神经支配在肿瘤转移过程中的作用， 肿瘤和神经免疫相互作用，并确定神经信号及其促转移机制， 作用，（ii）确定内皮细胞如何调节转移性肿瘤的神经支配，（iii）定义 区域化淋巴相互作用在驱动转移进展和抗转移免疫中的作用，（iv）评估 神经免疫和神经上皮相互作用对早期转移性播散和定植的作用， (v)鉴定驱动转移定植代谢物和蛋白质信号，（vi）发现肿瘤转录 这些因子和RNA结合蛋白在神经和代谢信号的下游起作用， 转移性基因表达程序，和（vii）确定标准化疗对这些的影响。 不同的细胞相互作用和转移进展的代谢决定因素。我们提议的MetNet中心 将增强我们对癌细胞与神经系统之间如何相互作用和串扰的理解 细胞、血管系统、脉管系统和免疫细胞使得转移性疾病出现。我们亦会评估 治疗如何影响特定的细胞-细胞和转移细胞的代谢相互作用，并提供对 原发微环境中特定细胞相互作用对转移性播散的影响，包括 早期传播。这些发现将产生一个综合的，系统水平的理解转移， 使新一代抗癌疗法的发展，防止关键的紧急协调 促转移相互作用。