Myofibroblasts in Gastrointestinal Cancers

这是来自哥伦比亚大学的一个高度合作的研究小组的肿瘤微环境网络的应用程序，他们在肿瘤微环境方面共同研究了5年多。该计划的重点是肌成纤维细胞（MF）/癌症相关成纤维细胞（CAF）在消化道癌症中的作用，包括胃癌，肝细胞癌和胰腺癌的研究。这三种癌症是最常见和最致命的实体瘤之一，有证据表明，每种癌症在早期都受到α-SMA+成纤维细胞的强烈促进。此外，最近的工作表明，螺杆菌依赖性胃癌是由CAF促进的，CAF来源于骨髓来源的间充质干细胞（MSC），并有助于MSC和肿瘤生态位;肝细胞癌是由微生物组和TLR 4信号转导激活的肌成纤维细胞促进的;消化道癌症中的CAF显示早期整体DNA低甲基化，伴有局灶性增益或启动子甲基化，这导致对DNA甲基化进一步丧失的独特易感性。根据这些意见和其他意见，提出了三个高度互动的项目。项目1（Wang）将进一步探索胃癌MF/CAFs的MSC起源、它们与微生物组信号的相互作用、它们对癌症生长的贡献以及低甲基化的机制;项目2（施瓦贝）将探索损伤相关分子模式（DAMP）、TLR 4和微生物组对肿瘤促进肌成纤维细胞生态位的作用;项目3（Tycko）将检查胰腺和肝细胞CAF低甲基化与基因表达和体内行为变化的关系，并检查CAF中地西他滨或条件性Dnmtl KO对预防肿瘤进展的作用。这三个项目将共同解决三大主题，即CAF的起源，肠道微生物组对其的激活以及DNA低甲基化的作用。这三个项目由麻省理工学院的行政/生物信息学核心和无菌小鼠核心支持。这三个项目是高度转化的，大量使用人体组织和消化道癌症的生理小鼠模型，并与人类胰腺癌患者的1期临床试验有关。

This is an application for the Tumor Microenvironment Network from a highly collaborative group of investigators from Columbia University who have worthed together for over 5 years on the tumor microenvironment. The focus of the program is the role of myofibroblasts (MF)/cancer-associated fibroblasts (CAF) in digestive cancers, and includes studies of gastric, hepatocellular and pancreatic cancer. The three cancers are among the most common and lethal of solid tumors, and evidence suggests that each is strongly promoted at early stages by alpha-SMA+ fibroblastic cells. In addition, recent work suggests that Helicobacter-dependent gastric cancer is promoted by CAFs that are derived from bone marrow derived mesenchymal stem cell (MSCs) and that contribute to the MSC and tumor niche; that hepatocellular cancer is promoted by myofibroblasts that are activated by the microbiome and TLR4 signaling; and that CAFs in digestive cancers show early global DNA hypomethylation with focal gains or promoter methylation, that results in a unique susceptibility to further loss of DNA methylation. Based on these and other observations, three highly interactive projects are proposed. Project 1 (Wang) will further explore the MSC origin of gastric cancer MF/CAFs, their interaction with microbiome signals, their contribution to cancer growth, and the mechanism of hypomethylation; Project 2 (Schwabe) will explore the role of damage-associated molecular patterns (DAMPs), TLR4, and the microbiome to the tumor-promoting myofibroblast niche; Project 3 (Tycko) will examine the relationship of pancreatic and hepatocellular CAF hypomethylation to changes in gene expression and in vivo behavior, and examine the effects of decitabine or conditional Dnmtl KO in CAFs on prevention of tumor progression. The three projects will jointly address the three major themes which are the origins of CAFs, their activation by the gut microbiome, and the role of DNA hypomethylation. The three projects are supported by an Administrative/Bioinformatics Core and by a Germ-Free Mouse Core at MIT. The three projects are highly translational with heavy use of human tissues and physiological mouse models of digestive cancers, and are linked to a Phase 1 clinical trial in human patients with pancreatic cancer.