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).

项目概要/摘要 胰腺导管腺癌（PDA）预计将成为癌症相关的第二大原因 2025年死亡，5年生存率仅为10%。胰腺疾病的进展部分是由 通过腺泡细胞转分化为胰腺化生管。化生簇细胞 (MTC) 是 化生上皮的一种特殊亚群，以前被描述为癌症干细胞 胰腺癌。簇细胞也称为孤立化学感应细胞，最早在啮齿动物管腔中发现 60 多年前，这些表面，包括鼻子、胃、肠和膀胱。他们的特点是 通过微绒毛“簇”伸入管腔，直到最近，研究才开始确定 不同器官中的正常簇细胞。这些研究确定簇细胞具有独特的功能，具体取决于 在它们所在的器官上。簇细胞在发育过程中存在于多种不同的器官中。然而， 研究表明，正常胰腺中不存在簇细胞。 MTC 仅存在于胰腺中 人类和小鼠的 PDA 进展过程中 PanIN 的作用。 此外，随着 PDA 进展为浸润性癌，胰腺中的 MTC 群消失 当使用簇细胞的规范标记时。我们对 MTC 在胰腺中的作用知之甚少，但之前 研究表明它们在 PDA 过程中发挥着祖细胞的作用。然而，这些研究并不仅仅 由于缺乏小鼠模型和复杂性，在 PDA 渐进模型中标记 MTC 的起源 离体培养它们。我们生成了一个独特的小鼠模型来驱动 MTC 的谱系追踪 PDA 和一种离体繁殖 MTC 的新培养方法。我有初步数据表明 MTC 是 不会随着 PDA 的进展而消失，而是随着 PanIns 去分化而转分化为神经内分泌细胞 转变为浸润性癌。我们与 Rosalie Sears 博士的合作出版了一份调查 NEC 的出版物， 它们是 PDA 中具有高度侵袭性的细胞类型。在本出版物中，我们确定 MYC 是 NEC开发。我们认为 MYC 是 MTC 转分化为 NEC 的驱动因素。这是 还已知 MTC 和 NEC 均源自腺泡细胞。这种转分化为 MTC 和 NEC 发生在化生发育过程中。我们的中心假设是 Myc 是 MTC 的驱动因素 转分化为 NEC。通过我们独特的谱系追踪小鼠模型，我们可以将 MTC 追踪到 PDA 中 当我们在 MTC 中特异性过度表达或敲低 Myc 并确定其在 Tuft 中的作用时，开发 神经内分泌转分化（TNT）。