Metaplastic Tuft Cells in Pancreatic Cancer

胰腺癌中的化生簇细胞

基本信息

批准号：
10581696
负责人：
Howard C Crawford
金额：
$ 46.5万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-09 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581696
关键词：
Ablation Acceleration Acetylcholine Acinar Cell Cancer Etiology Cell Differentiation process Cell physiology Cells Cessation of life Choline Cholinergic Agonists Complex Data Disease Disease Progression Duct (organ) structure Enterobacteria phage P1 Cre recombinase Environment Enzymes Epithelial Cells Epithelium Event Evolution G-Protein-Coupled Receptors GTP-Binding Proteins Genes Genetic Models Human Immune Immune response In Vitro Inflammatory KRASG12D Knock-out Lesion Macrophage Malignant Neoplasms Malignant neoplasm of pancreas Metaplasia Microtubules Modeling Molds Mus Nature Neoplasm Metastasis Neoplasms Neoplastic Cell Transformation Neuroendocrine Cell Neurons Organ Organoids Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pathology Pathway interactions Phosphotransferases Play Population Process Role Sampling Sensory Signal Transduction Survival Rate System Taste Buds Taste Perception Techniques Testing Tissues Transferase United States alpha-gustducin cell type checkpoint inhibition cytokine experimental study immunoregulation in vivo inducible Cre mouse model neoplastic neoplastic cell novel pancreatic ductal adenocarcinoma model pancreatic neoplasm preservation recombinase release factor response sensory system stem cells three dimensional cell culture tissue injury tissue repair tool transdifferentiation tumor tumor initiation tumor microenvironment tumor progression tumorigenesis

项目摘要

Abstract Pancreatic ductal adenocarcinoma (PDA) is the 3rd most common cause of cancer-related death in the United States. This dismal outcome is in part due to the lack of understanding of the unique pathology of PDA that includes pronounced epithelial plasticity and evolution of an extensive reactive fibroinflammatory stroma. We have discovered an unusual cell type within preneoplasia and neoplasia known as the metaplastic tuft cell (MTC), which has been proposed to act as both a tumor initiating cell and as a chemosensory cell that drives the fibroinflammatory host response. Normal tuft cells are found in normal glandular tissues and are marked by the expression of the microtubule kinase DCLK1. There they sample the luminal environment and respond to signals by modifying the Type 2 immune response. While there are no tuft cells found in the normal pancreas, they arise in a transdifferentiation event to become part of the metaplastic and neoplastic epithelium during oncogenesis or tissue injury. Besides their chemosensory function, they have been hypothesized to be a tumor initiating progenitor cell. In order to definitively determine the origins and functions of the metaplastic tuft cell, we have created a dual recombinase driven mouse model of pancreatic neoplasia combined with an inducible Cre recombinase that specifically targets MTCs that will allow us to alternatively trace and target the metaplastic tuft cells independent of neoplastic transformation in vivo. We have also devised human and mouse organoid culture systems that preserve tuft cell differentiation, so that we can study their genesis, fate and chemosensory function in more detail. Together, these tools will be used to rigorously determine the function of the metaplastic tuft cell and whether manipulating their functions can be used to treat pancreatic cancer.

抽象的胰腺导管腺癌（PDA）是癌症相关的第三个最常见原因在美国死亡。这种令人沮丧的结果部分是由于对 PDA的独特病理，包括明显的上皮可塑性和广泛的反应性炎性基质。我们在内部发现了一种不寻常的单元格肿瘤和肿瘤称为化生簇细胞（MTC），已提出充当引发细胞的肿瘤，又是驱动驱动的化学感应细胞纤维炎症宿主反应。在正常的腺组织中发现正常的簇细胞，是以微管激酶DCLK1的表达为特征。他们在那里采样了腔环境并通过修改2型免疫反应来响应信号。而有在正常胰腺中未发现簇细胞，它们在转分化事件中产生肿瘤发生或组织损伤期间的一部分化生和肿瘤上皮。除了它们的化学感应功能，已经假设它们是肿瘤的祖先细胞。为了确定确定化生簇细胞的起源和功能，我们已经创建了胰腺肿瘤的双重重组酶驱动的小鼠模型一种可诱导的CRE重组酶，专门针对MTC，使我们能够替代地跟踪并靶向与体内肿瘤转化无关的化生簇细胞。我们还设计了保留簇簇细胞的人类和小鼠器官培养系统分化，以便我们可以在更多的细节。这些工具将一起用于严格确定化生的功能簇细胞以及是否操纵其功能可用于治疗胰腺癌。