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: 10459722
• 负责人: Daniel James Salas-Escabillas
• 金额: $ 4.01万
• 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/10459722
• 关键词: Acinar Cell; Alleles; Automobile Driving; Bladder; CDKN2A gene; Cancer Etiology; Carcinoma; Cells; Cessation of life; Characteristics; Chromogranin A; Collaborations; Cues; Data; Development; Diagnosis; Disease; Down-Regulation; Duct (organ) structure; Early Diagnosis; Epithelial; Epithelial Cells; Generations; Genetic Models; Homeostasis; Human; Intestines; KRAS2 gene; KRASG12D; Label; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Metaplasia; Metastatic to; 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; Rodent; Role; Stomach; Surface; Survival Rate; Synaptophysin; System; TP53 gene; Testing; Tissues; Tumor-Suppressor Gene Inactivation; Up-Regulation; Work; c-myc Genes; 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; 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).

项目总结/摘要 胰腺导管腺癌（PDA）预计将成为癌症相关性的第二大原因。 2025年死亡，5年生存率仅为10%。胰腺疾病的进展部分是由 通过胰腺中腺泡细胞转分化为化生导管。化生簇细胞（MTCs）是 化生上皮的一个专门的亚群，以前被描述为癌症干细胞， 胰腺癌簇状细胞也被称为孤立的化学感受细胞，最早在啮齿动物的管腔中发现。 60多年前，它就已经在人体表面，包括鼻子、胃、肠和膀胱，进行了研究。它们的特征 直到最近，研究才开始确定微绒毛的作用， 不同器官中的正常簇细胞。这些研究表明，簇状细胞具有独特的功能， 它们所居住的器官上。在发育过程中，在几个不同的器官中发现了簇细胞;然而， 研究表明，正常胰腺中不存在丛状细胞。MTCs只存在于胰腺中 在人和小鼠PDA进展期间PanIN中的表达。 此外，随着PDA进展为浸润性癌，胰腺中的MTCs群体消失 当使用簇细胞的典型标记时。我们对MTCs在胰腺中的作用知之甚少， 研究表明它们在PDA期间作为祖细胞的作用。然而，这些研究并不完全 由于缺乏小鼠模型和复杂性， 离体培养。我们已经生成了一个独特的小鼠模型，以驱动MTCs的谱系追踪， PDA和一种离体增殖MTCs的新培养方法。我有初步的数据表明，MTCs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 转化为浸润性癌我们与Rosalie Sears博士的合作导致了一份研究NEC的出版物， 这是PDA中一种高度侵袭性的细胞类型。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MTCs转分化为NEC的驱动因素。是 也已知MTC和NEC均来源于腺泡细胞。这种向MTC和NEC的转分化 发生在化生发育期间。我们的中心假设是Myc是MTCs的驱动因素 转分化成NEC。通过我们独特的谱系追踪小鼠模型，我们可以追踪MTCs进入PDA 当我们特异性地在MTCs中过表达或敲低Myc并确定其在Tuft中的作用时， 神经内分泌转分化（TNT）。