期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 48, 页码 18913-18918出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0810097105
关键词
lineage tracing; transdifferentiation; precursor lesions; pancreatic cancer
资金
- National Institutes of Health [CA113669, DK072532, DK61215, DK56211, DK55489, CA124586]
- Sol Goldman Pancreatic Cancer Research Center
- Lustgarten Foundation for Pancreatic Cancer Research
- Phi Beta Psi Sorority Cancer Fund
- Postdoctoral Program of the German Academic Exchange Service
- Ruth L. Kirschstein National Research Service Award [T32DK007713]
- Paul Neumann Professorship in Pancreatic Cancer Research
Pancreatic ductal adenocarcinoma (PDAC) is believed to arise through a multistep model comprised of putative precursor lesions known as pancreatic intraepithelial neoplasia (PanIN). Recent genetically engineered mouse models of PDAC demonstrate a comparable morphologic spectrum of murine PanIN (mPanIN) lesions. The histogenesis of PanIN and PDAC in both mice and men remains controversial. The most faithful genetic models activate an oncogenic Kras(G12D) knockin allele within the pdx1- or ptf1a/p48-expression domain of the entire pancreatic anlage during development, thus obscuring the putative cell(s)-of-origin from which subsequent mPanIN lesions arise. In our study, activation of this knockin Kras(G12D) allele in the Elastase- and Mist1-expressing mature acinar compartment of adult mice resulted in the spontaneous induction of mPanIN lesions of all histological grades, although invasive carcinomas per se were not seen. We observed no requirement for concomitant chronic exocrine injury in the induction of mPanIN lesions from the mature acinar cell compartment. The acinar cell derivation of the mPanINs was established through lineage tracing in reporter mice, and by microdissection of lesional tissue demonstrating Cre-mediated recombination events. In contrast to the uniformly penetrant mPanIN phenotype observed following developmental activation of KrasG12D in the Pdx1-expressing progenitor cells, the Pdx1-expressing population in the mature pancreas (predominantly islet beta cells) appears to be relatively resistant to the effects of oncogenic Kras. We conclude that in the appropriate genetic context, the differentiated acinar cell compartment in adult mice retains its susceptibility for spontaneous transformation into mPanIN lesions, a finding with potential relevance vis-a-vis the origins of PDAC.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据