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

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
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-12 至 2025-09-11

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英文摘要
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).
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Understanding the Fate of Metaplastic Tuft Cells in the Progression of Pancreatic Cancer
  • 批准号:
    10459722
  • 项目类别:
  • 资助金额:
    $4.01万
  • 财政年份:
    2022
  • 负责人:
    Daniel James Salas-Escabillas
  • 依托单位:
海外基金