Center for Systems-level Study of Metastasis

转移系统级研究中心

基本信息

批准号：
10688112
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
项目类别：
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/10688112
关键词：
Automobile Driving Bioinformatics Biological Biology Breast Cancer Cell Cell Communication Cell physiology Cells Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collaborations 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 Metabolite Interaction Methods Molecular Neoplasm Metastasis Nervous System Neuroepithelial Neuroimmune Neurons Nutrient 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 Technology analytical method biological systems cancer cell cancer therapy cell type chemotherapy colorectal cancer metastasis experience innovation insight malignant breast neoplasm multidisciplinary nerve supply neural neurotransmission novel prevent programs response single cell sequencing success therapeutic target tool transcription factor treatment response tumor tumor immunology tumor metabolism tumor progression

项目摘要

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.

项目摘要：转移性疾病是一个复杂、动态和突发的过程，需要集体和许多细胞类型、代谢物和宿主之间存在大量的临床相互作用。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。这些细胞相互作用可能会影响转移进展、对治疗的反应和转移然而，我们对这些组成部分如何协调调节的了解有限。该应用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方法应用于定义神经细胞、淋巴管、免疫细胞和代谢物的动态和突发机制相互作用以协调调节转移进展——有助于系统层面的理解我们的目标是（i）通过表征神经支配来定义神经支配在转移进展中的作用。肿瘤和神经免疫相互作用并识别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扩散和定植的作用， (v) 识别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，以驱动新兴的亲转移基因表达计划，以及 (vii) 确定标准化疗对这些计划的影响我们提议的 MetNet 中心的不同细胞相互作用和代谢决定因素。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我们还将评估细胞、淋巴管、脉管系统和免疫细胞是否会出现转移性疾病。治疗如何影响转移细胞的特定细胞间和代谢相互作用，并提供对转移细胞的见解原发微环境中特定细胞相互作用对转移扩散的影响，包括这些发现将产生对转移的综合、系统层面的理解，促进新一代抗癌疗法的开发，以防止关键的紧急协调促转移相互作用。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics.

亮氨酰-tRNA 合成酶是乳腺癌中的肿瘤抑制因子，可调节密码子依赖性翻译动力学。

DOI：
发表时间：
2022-03
期刊：
影响因子：
21.3
作者：
Passarelli, Maria C;Pinzaru, Alexandra M;Asgharian, Hosseinali;Liberti, Maria V;Heissel, Søren;Molina, Henrik;Goodarzi, Hani;Tavazoie, Sohail F
通讯作者：
Tavazoie, Sohail F

Functional genetic screen identifies ITPR3/calcium/RELB axis as a driver of colorectal cancer metastatic liver colonization.

功能性遗传筛查将 ITPR3/钙/RELB 轴确定为结直肠癌转移性肝定植的驱动因素。

DOI：
10.1016/j.devcel.2022.04.010
发表时间：
2022-05-09
期刊：
Developmental cell
影响因子：
11.8
作者：
Moy, Ryan H.;Nguyen, Alexander;Loo, Jia Min;Yamaguchi, Norihiro;Kajba, Christina M.;Santhanam, Balaji;Ostendorf, Benjamin N.;Wu, Y. Gloria;Tavazoie, Saeed;Tavazoie, Sohail F.
通讯作者：
Tavazoie, Sohail F.