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

项目摘要/摘要 据预测，胰腺导管腺癌(Pda)将成为与癌症相关的第二大病因。 2025年死亡，5年存活率只有10%。胰腺疾病的发展在一定程度上是由 通过胰腺中腺泡细胞的转化分化为化生导管。化生绒毛细胞(MTCs)是 一种特殊的化生上皮亚群，以前被描述为癌症干细胞 胰腺癌。丛状细胞也被称为孤立的化学感觉细胞，最早是在啮齿动物的腔内发现的。 表面，包括鼻子、胃、肠和膀胱，在60多年前。他们的特点是 通过微绒毛进入管腔，直到最近，才有研究开始确定 不同器官中的正常簇状细胞。这些研究确定了丛生细胞具有独特的功能，依赖于 在它们所在的器官上。在发育过程中，丛生细胞在几个不同的器官中被发现；然而， 研究表明，正常胰腺中不存在簇状细胞。巨噬细胞仅存在于胰腺中。 在人类和小鼠的PDA进展过程中的Panins。 此外，随着pda进展为浸润性癌，胰腺中的mtc数量消失。 当使用簇状细胞的规范标记时。我们对MTCs在胰腺中的作用知之甚少，但在此之前 研究表明，它们在PDA过程中扮演着祖细胞的角色。然而，这些研究并不完全 由于缺乏小鼠模型和复杂性，在进展性PDA模型中标记MTCs 在体外培养它们。我们已经生成了一种独特的小鼠模型来驱动MTC的血统追踪 PDA和一种新的体外培养MTCs的方法。我有初步数据表明，MTC 不是随着PDA的进展而消失，而是随着Panins的去分化而转分化为神经内分泌细胞 转化为浸润性癌。我们与罗莎莉·西尔斯博士的合作导致了一份研究NECS的出版物， 它们是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向NECs转分化的驱动因素。它是 已知MTCs和NECs均来源于腺泡细胞。这种向MTC和NECS的转变 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 转化为NECS。通过我们独特的血统追踪小鼠模型，我们可以将MTC追踪到PDA 当我们在MTC中过表达或敲除Myc并确定其在Tuft中的角色时的发展 神经内分泌转分化(TNT)。

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).