Project-2:Defining the role of compartmentalized neuro-lymphatic networks on CRC and metastatic progression

项目 2：定义分区神经淋巴网络对 CRC 和转移进展的作用

基本信息

批准号：
10688116
负责人：
Daniel S Mucida
金额：
$ 37.48万
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/10688116
关键词：
Address Affect Antigens Antitumor Response Architecture Bioinformatics Biology Cell Communication Cell Separation Cells Cellular Metabolic Process Collection Colorectal Cancer Communication Critical Pathways Cues Data Diet Distal Drainage procedure Early identification Enteral Environment Epithelial Cells Equilibrium Event Food Hypersensitivity Gastrointestinal tract structure Gene Expression Genetic Gnotobiotic Image Imaging Techniques Immune Immune response Immune system Immunologic Surveillance Immunologics In Vitro Indigenous Inflammation Inflammatory Inflammatory Bowel Diseases Intestinal Neoplasms Intestines Invaded Irritable Bowel Syndrome Label Liver Location Lymph Node Drainage Lymphatic Lymphatic System Malignant Neoplasms Maps Mediating Metastatic Neoplasm to the Liver Modernization Molecular Mucous Membrane Neoplasm Metastasis Neuroimmune Neurons Patients Persons Physiology Play Population Primary Neoplasm Resistance Role Route Signal Transduction Site Submucosa System Tissues Translating Tumor Immunity United States Visualization adaptive immunity cell injury cell killing colorectal cancer metastasis colorectal cancer prevention colorectal cancer progression cytokine draining lymph node enteric pathogen gain of function genetic approach imaging approach intestinal villi loss of function lymph nodes lymphatic drainage lymphatic vessel metabolomics metastatic colorectal microbial microbiota mouse model neuronal cell body neuronal circuitry novel novel strategies prevent response screening tool transcriptomics translatome tumor tumor microenvironment tumor progression

项目摘要

Colorectal cancer (CRC) is the second most deadly cancer in the United States, affecting over 140,000 people each year, killing approximately 50,000 in the US, largely by metastatic progression. The intestine hosts the body’s largest collection of immune cells, maintained in close proximity to foreign antigens from the diet, enriched in the proximal regions, and microbiota, which accumulate in the distal regions. The vast and highly connected gut lymphatic vessels form a major cell- and antigen transport route to the draining lymph nodes, responsible for the initiation of adaptive immunity, which could play four roles in regulating colorectal cancer metastasis: immune cells could (i) prevent CRC progression and early dissemination or metastasis by immune-cell killing (ii) promote CRC progression and metastasis through release of inflammatory cytokines, (iii) prevent metastatic colonization in the liver, or (iv) promote metastatic colonization in the liver. We provide data that compartmentalization of intestinal lymphatic drainage to functionally distinct lymph nodes facilitates the simultaneous induction of immune-suppressive and inflammatory immune responses in the gut; however, the relevance of gut lymphatics to CRC and metastasis remains underexplored. In addition to compartmentalized lymphatic networks, the gut also hosts a large number of enteric neurons functionally tuned to each region they occupy. Using retrograde tracing from distinct intestinal regions and specific cell-sorting independent transcriptomics, we uncovered novel neuronal circuits and a role for enteric neurons in sensing perturbations in the intestinal tissue; whether enteric neurons sense and modulate CRC metastatic progression remains unknown. Overall, Project 2 is focused on understanding how enteric-associated neurons sense and provide signals that regulate CRC progression and liver dissemination and how compartmentalized intestinal lymphatic drainage of primary tumor and metastatic liver sites regulate anti-tumor responses and early dissemination. In Aim 1, we hypothesize that primary CRC, as well as liver metastasis, are specifically sensed by populations of enteric-associated neurons, which in turn, influence tumor and metastatic progression. This question will be addressed using tools to visualize and circuit- map, single cell and active translating transcriptomics, and chemogenetic approaches targeting specific neuronal subsets. In Aim 2, we hypothesize that the intestinal lymphatic system communicates primary CRC and early metastatic seeding to the local and systemic immune system, modulating anti-tumor responses. This will be addressed combining modern clearing and live imaging techniques, single cell transcriptomics and novel immune cell-interaction approaches. By combining these approaches, expertise of Mucida lab, with Sohail Tavazoie lab’s expertise in cancer and metastasis biology (Project 1), the Birsoy lab’s expertise in in vitro screenings and cell metabolism (Project 3), and the Cao and Saeed Tavazoie labs expertise in single-cell and bioinformatics analyses, we seek to determine the role of neuro-lymphatic networks in CRC progression and metastatic formation.

结直肠癌 (CRC) 是美国第二大致命癌症，影响超过 140,000 人每年，美国约有 50,000 人死亡，主要是由于转移性进展。身体最大的免疫细胞集合，与饮食中的外来抗原保持密切接触，丰富了近端区域的微生物群和远端区域积累的微生物群。肠道淋巴管形成了通往引流淋巴结的主要细胞和抗原运输路线，负责适应性免疫的启动，在调节结直肠癌转移中发挥四个作用：细胞可以 (i) 通过免疫细胞杀伤来预防 CRC 进展和早期传播或转移 (ii) 促进通过释放炎症细胞因子促进结直肠癌进展和转移，(iii) 防止转移定植在肝脏中，或（iv）促进肝脏中的转移定植。我们提供了划分的数据。肠道淋巴引流到功能不同的淋巴结有利于同时诱导然而，肠道中的免疫抑制和炎症免疫反应；肠道淋巴管的相关性；除了分区的淋巴网络外，肠道对结直肠癌和转移的影响仍未得到充分研究。还拥有大量肠道神经元，这些神经元通过逆行功能对其所占据的每个区域进行功能调整。从不同的肠道区域和特定的细胞分选独立转录组学追踪，我们发现了新的神经元回路以及肠道神经元在感知肠道组织扰动中的作用；总体而言，项目 2 的重点是神经元感知和调节 CRC 转移进展。了解肠相关神经元如何感知和提供调节 CRC 进展的信号，以及肝脏播散以及如何区分原发性肿瘤和转移性肿瘤的肠道淋巴引流肝脏部位调节抗肿瘤反应和早期传播在目标 1 中，我们追求原发性 CRC，以及肝转移，被肠道相关神经元群体特异性感知，反过来，将使用可视化和电路工具来解决这个问题。图谱、单细胞和主动翻译转录组学以及针对特定神经元的化学遗传学方法在目标 2 中，我们追求肠道淋巴系统沟通原发性 CRC 和早期 CRC。转移到局部和全身免疫系统，调节抗肿瘤反应。解决了现代透明化和实时成像技术、单细胞转录组学和新型免疫相结合的问题通过将这些方法、Mucida 实验室的专业知识与 Sohail Tavazoie 实验室的相结合。癌症和转移生物学方面的专业知识（项目 1），Birsoy 实验室在体外筛选和细胞方面的专业知识新陈代谢（项目 3），以及 Cao 和 Saeed Tavazoie 实验室在单细胞和生物信息学方面的专业知识通过分析，我们试图确定神经淋巴网络在结直肠癌进展和转移中的作用形成。