Center for Systems-level Study of Metastasis

项目摘要：转移性疾病是一个复杂、动态和紧急的过程，需要集体和 多种细胞类型、代谢物和宿主之间的协调相互作用。有相当多的诊所- 神经支配、淋巴相互作用、代谢物关键作用的病理和实验证据 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， 这些细胞间的相互作用可能形成转移进展、对治疗的反应和转移 传播。然而，我们对这些组成部分如何协调调节的了解有限 转移的进展。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、大规模并行单细胞测序和生物体方法应用于 确定神经细胞、淋巴管、免疫细胞和代谢物的动态和紧急机制 相互作用以协调调节转移进展-有助于在系统水平上理解 转移。我们的目标是：(I)通过表征神经功能，明确神经支配在转移过程中的作用。 肿瘤与神经免疫的相互作用和神经信号的识别及其促转移机制 作用，(Ii)确定内皮细胞如何调节转移性肿瘤的神经支配，(Iii)确定 区域性淋巴相互作用在推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细胞相互作用在早期转移扩散和定植中的作用 (V)确定驱动转移定植的代谢物和蛋白质信号，(Vi)发现肿瘤转录 作用于神经和代谢信号下游的因子和RNA结合蛋白，推动新出现的亲 转移基因表达计划，以及(Vii)确定标准化疗对这些指标的影响 转移进展的不同细胞相互作用和代谢决定因素。我们建议的MetNet中心 将加深我们对癌细胞与神经系统之间的相互作用和串扰的理解 细胞、淋巴管、血管和免疫细胞使转移性疾病的出现成为可能。我们还将评估 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扩散的影响，包括 早期传播。这些发现将产生对转移的综合、系统水平的理解， 能够开发新一代抗癌疗法，防止危急紧急情况协调 促进转移的相互作用。

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.