Mouse models for pancreatic ductal adenocarcinoma are affected by the cre-driver used to promote KRASG12D activation.

IF 7.1 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Fatemeh Mousavi, Joyce Thompson, Justine Lau, Nur Renollet, Mickenzie B Martin, Jake McGue, Oneeb Hassan, Timothy Frankel, Parisa Shooshtari, Christopher L Pin, Filip Bednar
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引用次数: 0

Abstract

Background and aims: The fundamental biology of pancreatic ductal adenocarcinoma has been greatly impacted by the characterization of genetically engineered mouse models that allow temporal and spatial activation of oncogenic KRAS (KRASG12D). One of the most commonly used models involves targeted insertion of a cre-recombinase into the Ptf1a gene. However, this approach disrupts the Ptf1a gene, resulting in haploinsufficiency that likely affects sensitivity to oncogenic KRAS (KRASG12D). This study aims to determine if Ptf1a haploinsufficiency affected the acinar cell response to KRASG12D before and after induction of pancreatic injury.

Methods: We performed morphological and molecular analysis of three genetically engineered mouse models that express a tamoxifen-inducible cre-recombinase to activate KrasG12D in acinar cells of the pancreas. The cre-recombinase was targeted to the acinar-specific transcription factor genes, Ptf1a or Mist1/Bhlha15, or expressed within a BAC-derived Elastase transgene. Histological and RNA-seq analyses were used to delineate differences between the models.

Results: Up to two months after tamoxifen induction of KRASG12D, morphological changes were negligible. However, induction of pancreatic injury by cerulein resulted in widespread PanIN lesions in Ptf1acreERT pancreata within seven days and maintained for at least five weeks post-injury, which was not seen in the models with two functional Ptf1a alleles. RNA-seq analysis prior to injury induction suggested Ptf1acreERT and Mist1creERT mice have unique profiles of gene expression that predict a differential response to injury. Multiplex analysis of pancreatic tissue confirmed different inflammatory responses between the models.

Conclusions: These findings suggest Ptf1a haploinsufficiency in Ptf1acreERT mouse models promotes KRASG12D priming of genes for promotion of PDAC.

胰腺导管腺癌小鼠模型受用于促进 KRASG12D 激活的 cre 驱动程序的影响。
背景和目的:基因工程小鼠模型可在时间和空间上激活致癌基因 KRAS (KRASG12D),其特征对胰腺导管腺癌的基础生物学产生了巨大影响。最常用的模型之一是在 Ptf1a 基因中定向插入 cre 重组酶。然而,这种方法会破坏 Ptf1a 基因,导致单倍体缺陷,从而可能影响对致癌 KRAS(KRASG12D)的敏感性。本研究旨在确定在诱导胰腺损伤前后,Ptf1a单倍体缺陷是否会影响尖突细胞对KRASG12D的反应:我们对三种基因工程小鼠模型进行了形态学和分子分析,这些模型表达了他莫昔芬诱导的cre-重组酶,以激活胰腺尖突细胞中的KrasG12D。cre-重组酶靶向于胰腺尖突特异性转录因子基因Ptf1a或Mist1/Bhlha15,或在BAC衍生的弹性蛋白酶转基因中表达。组织学和RNA-seq分析用于确定不同模型之间的差异:结果:他莫昔芬诱导KRASG12D两个月后,其形态学变化可忽略不计。然而,在Ptf1acreERT胰腺中,用cerulein诱导胰腺损伤会在七天内导致广泛的PanIN病变,并在损伤后至少维持五周,这在具有两个功能性Ptf1a等位基因的模型中是看不到的。损伤诱导前的RNA-seq分析表明,Ptf1acreERT和Mist1creERT小鼠具有独特的基因表达谱,可预测对损伤的不同反应。对胰腺组织的多重分析证实了两种模型之间不同的炎症反应:这些研究结果表明,Ptf1acreERT 小鼠模型中的 Ptf1a 单倍性缺失会促进 KRASG12D 启动基因,从而诱发 PDAC。
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来源期刊
CiteScore
13.00
自引率
2.80%
发文量
246
审稿时长
42 days
期刊介绍: "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.
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