Understanding the Fate of Metaplastic Tuft Cells in the Progression of Pancreatic Cancer

了解化生簇细胞在胰腺癌进展中的命运

• 批准号: 10724235
• 负责人: Daniel James Salas-Escabillas
• 金额: $ 4.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2025-09-11
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724235
• 关键词: Ablation; Acinar Cell; Alleles; Automobile Driving; Bladder; CDKN2A gene; Cancer Etiology; Carcinoma; Cell Communication; Cells; Cessation of life; Characteristics; Chromogranin A; Collaborations; Cues; Data; Development; Diagnosis; Disease; Down-Regulation; Duct (organ) structure; Early Diagnosis; Epithelial Cells; Epithelium; Generations; Genetic Models; Homeostasis; Human; Intestines; KRAS2 gene; KRASG12D; Label; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Metaplasia; Methods; Modeling; Mus; Mutation; Neoplasm Metastasis; Neoplasms; Neuroendocrine Cell; Neurosecretory Systems; Nose; Oncogenes; Organ; Organoids; Pancreas; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Population; Population Heterogeneity; Property; Publications; Reporter; Repression; Rodent; Role; Sensory; Stomach; Surface; Survival Rate; Synaptophysin; System; TP53 gene; Testing; Tissues; Tumor-Suppressor Gene Inactivation; Up-Regulation; Work; c-myc Genes; cancer initiation; cancer stem cell; cancer type; cell type; cellular microvillus; chronic pancreatitis; daughter cell; detection method; effective therapy; epithelial to mesenchymal transition; experimental study; knock-down; live cell imaging; mouse model; novel; overexpression; pancreatic cancer model; pancreatic ductal adenocarcinoma model; progenitor; recombinase; stem cell biomarkers; stem cells; transcriptomics; transdifferentiation; tumor initiation; tumor progression

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDA) is predicted to become the second leading cause of cancer-related death in 2025 and has a 5-year survival rate of only 10%. The progression of pancreatic disease is partly driven by the transdifferentiation of acinar cells into metaplastic ducts in the pancreas. Metaplastic tuft cells (MTCs) are a specialized subset of the metaplastic epithelium that has been previously described as cancer stem cells in pancreatic cancer. Also known as solitary chemosensory cells, tuft cells were first discovered in rodent luminal surfaces, including the nose, stomach, intestine, and bladder, more than 60 years ago. They are characterized by the “tuft” of microvilli reaching into the lumen and, only recently, have studies started to determine the role of normal tuft cells in different organs. These studies determined that tuft cells have unique functions depending on the organ in which they reside. Tuft cells are found in several various organs during development; however, studies have shown that tuft cells are not present in a normal pancreas. MTCs are only present in the pancreas in PanINs during PDA progression in both humans and mice. Furthermore, the population of MTCs in the pancreas disappears as PDA progresses into invasive carcinoma when using canonical markers of tuft cells. We know little about the role of MTCs in the pancreas, but prior studies have suggested their role as a progenitor cell during PDA. However, these studies do not exclusively mark MTCs during their genesis in a progressive model of PDA due to a lack of mouse models and the complexity of culturing them ex vivo. We have generated a unique mouse model to drive lineage tracing of MTCs during PDA and a novel culture method to propagate MTCs ex vivo. I have preliminary data to suggest that MTCs are not disappearing as PDA progresses but transdifferentiate into neuroendocrine cells as PanIns dedifferentiate into invasive carcinoma. Our collaborations with Dr. Rosalie Sears have led to a publication investigating NECs, which are a highly aggressive cell type in PDA. In this publication, we establish that MYC is a driving factor of NEC development. We believe that MYC is a driving factor in the transdifferentiation of MTCs into NECs. It is also known that both MTCs and NECs derive from the acinar cells. This transdifferentiation into MTCs and NECs occurs during metaplastic development. Our central hypothesis is that Myc is a driving factor in MTCs transdifferentiating into NECs. Through our unique lineage trace mouse model, we can trace MTCs into PDA development when we overexpress or knockdown Myc in MTCs specifically and determine its role in Tuft to Neuroendocrine Transdifferentiation (TNT).

项目摘要/摘要 预计胰腺导管腺癌（PDA）被预测成为癌症相关的第二大原因 2025年的死亡人数仅为5年，仅为10％。胰腺疾病的进展部分是驱动的 通过将腺泡细胞转分化为胰腺中的化生管道。化生簇细胞（MTC）是 转移上皮的专门子集，以前已被描述为癌细胞中的癌细胞 胰腺癌。也称为固体化学感应细胞，首先在啮齿动物的腔中发现了簇细胞 60多年前，包括鼻子，摊位，肠和膀胱在内的表面。它们是特征的 通过微绒毛的“​​簇”伸入管腔，直到最近才开始研究 不同器官中的正常簇状细胞。这些研究确定簇细胞具有独特的功能 在它们居住的器官上。在发育过程中发现簇状细胞在几个不同的器官中发现。然而， 研究表明，簇状细胞不存在于正常胰腺中。 MTC仅存在于胰腺中 在人类和小鼠的PDA进展过程中，在Panins中。 此外，随着PDA发展为侵入性癌，胰腺中MTC的种群消失了 当使用簇状细胞的规范标记时。我们对MTC在胰腺中的作用一无所知，但之前 研究表明，它们在PDA期间作为祖细胞的作用。但是，这些研究并不完全 由于缺乏小鼠模型和复杂性，在PDA的渐进模型中，Mark MTC在其起源期间 在体内培养它们。我们已经生成了一个独特的鼠标模型来驱动MTC的谱系跟踪 PDA和一种传播MTC的新型培养方法。我有初步数据，建议MTC是 随着PDA的进展，不消失，而是转变为神经内分泌细胞，因为panins去分化 进入侵入性癌。我们与罗莎莉·西尔斯（Rosalie Sears）博士的合作导致了一份出版物，正在调查NEC， 这是PDA中高度侵略性的细胞类型。在本出版物中，我们确定MYC是一个驱动因素 NEC开发。我们认为，MYC是MTC转变为NEC的驱动因素。这是 也知道MTC和NEC均来自腺泡细胞。这种转变为MTC和NEC 发生在变质发展期间。我们的中心假设是MYC是MTC中的驱动因素 转变为NEC。通过我们独特的谱系跟踪鼠标模型，我们可以将MTC追踪到PDA中 当我们专门在MTC中过表达或敲除MYC并确定其在簇中的作用时，开发 神经内分泌转分化（TNT）。