Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice
Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice
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DOI：
10.1073/pnas.0810097105
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发表时间：
2008-12-02
影响因子：
11.1
通讯作者：
Maitra, Anirban
中科院分区：
文献类型：
--
作者：
Habbe, Nils;Shi, Guanglu;Maitra, Anirban
胰腺导管腺癌(PDAC)被认为是通过一个由胰腺上皮内瘤变(Panin)的假定前体病变组成的多步骤模型而产生的。最近的PDAC基因工程小鼠模型显示出类似的小鼠Panin(MPanIN)病变的形态图谱。Panin和PDAC在小鼠和人类中的组织发生仍然存在争议。最忠实的遗传模型在发育过程中激活整个胰腺原基的PDX1或ptf1a/p48表达区域内的致癌Kras(G12D)敲击等位基因，从而掩盖了随后发生mPanIN病变的假定起源细胞(S)。在我们的研究中，这种敲门Kras(G12D)等位基因在成年小鼠表达弹性蛋白酶和Mist1的成熟腺泡间隔中的激活导致了所有组织学级别的mPanIN病变的自发诱导，尽管本身没有发现浸润性癌。我们观察到，在从成熟的腺泡细胞室诱导mPanIN损伤的过程中，不需要伴随慢性外分泌损伤。MPanINs的腺泡细胞来源是通过对报告小鼠的谱系追踪和对证明Cre介导的重组事件的皮损组织的显微解剖来建立的。与在表达Pdx1的前体细胞中观察到的KrasG12D发育激活后观察到的均匀渗透的mPanIN表型相反，在成熟胰腺(主要是胰岛β细胞)中表达Pdx1的群体似乎对致癌Kras的影响相对耐受。我们的结论是，在适当的遗传背景下，成年小鼠分化的腺泡细胞室保持其自发转化为mPanIN病变的敏感性，这一发现与PDAC的起源有潜在的相关性。
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.