scholarly journals The Use of Genetically Engineered Mouse Models for Studying the Function of Mutated Driver Genes in Pancreatic Cancer

2019 ◽  
Vol 8 (9) ◽  
pp. 1369 ◽  
Author(s):  
Weng ◽  
Lin ◽  
Cheng
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Models ◽  
Cancer Biology ◽  
Gene Knockout ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Neoplastic Progression ◽  
Driver Genes ◽  
Genetically Engineered Mouse Models ◽  
Oncology Research

Pancreatic cancer is often treatment-resistant, with the emerging standard of care, gemcitabine, affording only a few months of incrementally-deteriorating survival. Reflecting on the history of failed clinical trials, genetically engineered mouse models (GEMMs) in oncology research provides the inspiration to discover new treatments for pancreatic cancer that come from better knowledge of pathogenesis mechanisms, not only of the derangements in and consequently acquired capabilities of the cancer cells, but also in the aberrant microenvironment that becomes established to support, sustain, and enhance neoplastic progression. On the other hand, the existing mutational profile of pancreatic cancer guides our understanding of the disease, but leaves many important questions of pancreatic cancer biology unanswered. Over the past decade, a series of transgenic and gene knockout mouse modes have been produced that develop pancreatic cancers with features reflective of metastatic pancreatic ductal adenocarcinoma (PDAC) in humans. Animal models of PDAC are likely to be essential to understanding the genetics and biology of the disease and may provide the foundation for advances in early diagnosis and treatment.

scholarly journals Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 71
Author(s):  
Yuriko Saiki ◽  
Can Jiang ◽  
Masaki Ohmuraya ◽  
Toru Furukawa
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Models ◽  
Tumor Biology ◽  
Genetically Engineered ◽  
Lineage Tracing ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Precursor Lesions ◽  
Genetically Engineered Mouse Models ◽  
Molecular Alterations

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, and the seventh leading cause of cancer-related deaths worldwide. An improved understanding of tumor biology and novel therapeutic discoveries are needed to improve overall survival. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. Advanced GEMMs permit the temporally and spatially controlled manipulation of multiple target genes using a dual-recombinase system or CRISPR/Cas9 gene editing. GEMMs that express fluorescent proteins allow cell lineage tracing to follow tumor growth and metastasis to understand the contribution of different cell types in cancer progression. GEMMs are widely used for therapeutic optimization. In this review, we summarize the main molecular alterations found in pancreatic neoplasms, developed GEMMs, and the contribution of GEMMs to the current understanding of PDAC pathobiology. Furthermore, we attempted to modify the categorization of altered driver genes according to the most updated findings.

Pancreatic Intraepithelial Neoplasia and Pancreatic Tumorigenesis: Of Mice and Men

2009 ◽  
Vol 133 (3) ◽  
pp. 375-381 ◽  
Author(s):  
Niki A. Ottenhof ◽  
Anya N. A. Milne ◽  
Folkert H. M. Morsink ◽  
Paul Drillenburg ◽  
Fiebo J. W. ten Kate ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Progression ◽  
Mouse Models ◽  
Intraepithelial Neoplasia ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Intraepithelial Neoplasia ◽  
Pancreatic Carcinogenesis ◽  
Genetically Engineered Mouse Models

Abstract Context.—Pancreatic cancer has a poor prognosis with a 5-year survival of less than 5%. Early detection is at present the only way to improve this outlook. This review focuses on the recent advances in our understanding of pancreatic carcinogenesis, the scientific evidence for a multistaged tumor progression, and the role genetically engineered mouse models can play in recapitulating the natural course and biology of human disease. Objectives.—To illustrate the stepwise tumor progression of pancreatic cancer and genetic alterations within the different stages of progression and to review the findings made with genetically engineered mouse models concerning pancreatic carcinogenesis. Data Sources.—A review of recent literature on pancreatic tumorigenesis and genetically engineered mouse models. Conclusions.—Pancreatic cancer develops through stepwise tumor progression in which preinvasive stages, called pancreatic intraepithelial neoplasia, precede invasive pancreatic cancer. Genetic alterations in oncogenes and tumor suppressor genes underlying pancreatic cancer are also found in pancreatic intraepithelial neoplasia. These mutations accumulate during progression through the consecutive stages of pancreatic intraepithelial neoplasia lesions. Also in genetically engineered mouse models of pancreatic ductal adenocarcinoma, tumorigenesis occurs through stepwise progression via consecutive mouse pancreatic intraepithelial neoplasia, and these models provide important tools for clinical applications. Nevertheless differences between mice and men still remain.

Development of multi-drug loaded PEGylated nanodiamonds to inhibit tumor growth and metastasis in genetically engineered mouse models of pancreatic cancer

Nanoscale ◽  
2019 ◽  
Vol 11 (45) ◽  
pp. 22006-22018 ◽  
Author(s):  
Vijay Sagar Madamsetty ◽  
Krishnendu Pal ◽  
Sandeep Keshavan ◽  
Thomas R. Caulfield ◽  
Shamit Kumar Dutta ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Models ◽  
Genetically Engineered ◽  
Inhibit Tumor Growth ◽  
Schematic Representation ◽  
Genetically Engineered Mouse Models ◽  
Tumor Growth And Metastasis ◽  
Nano Formulation ◽  
Immune Competent Mouse

Schematic representation demonstrating the fabrication and in vivo evaluation of an immune-modulatory nano-formulation consisting of irinotecan and curcumin in immune-competent mouse models of pancreatic adenocarcinoma.

scholarly journals How Genetically Engineered Mouse Tumor Models Provide Insights Into Human Cancers

2011 ◽  
Vol 29 (16) ◽  
pp. 2273-2281 ◽  
Author(s):  
Katerina Politi ◽  
William Pao
Keyword(s):  
Mouse Models ◽  
Cancer Biology ◽  
Human Cancer ◽  
Genetically Engineered ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Genetically Engineered Mouse Models ◽  
Human Cancers ◽  
Chemically Induced

Genetically engineered mouse models (GEMMs) of human cancer were first created nearly 30 years ago. These early transgenic models demonstrated that mouse cells could be transformed in vivo by expression of an oncogene. A new field emerged, dedicated to generating and using mouse models of human cancer to address a wide variety of questions in cancer biology. The aim of this review is to highlight the contributions of mouse models to the diagnosis and treatment of human cancers. Because of the breadth of the topic, we have selected representative examples of how GEMMs are clinically relevant rather than provided an exhaustive list of experiments. Today, as detailed here, sophisticated mouse models are being created to study many aspects of cancer biology, including but not limited to mechanisms of sensitivity and resistance to drug treatment, oncogene cooperation, early detection, and metastasis. Alternatives to GEMMs, such as chemically induced or spontaneous tumor models, are not discussed in this review.

scholarly journals Genetically engineered mouse models in oncology research and cancer medicine

2016 ◽  
Vol 9 (2) ◽  
pp. 137-153 ◽  
Author(s):  
Kelly Kersten ◽  
Karin E Visser ◽  
Martine H Miltenburg ◽  
Jos Jonkers
Keyword(s):  
Mouse Models ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Oncology Research ◽  
Cancer Medicine

scholarly journals Autoantibodies to Ezrin are an early sign of pancreatic cancer in humans and in genetically engineered mouse models

2013 ◽  
Vol 6 (1) ◽  
pp. 67 ◽  
Author(s):  
Michela Capello ◽  
Paola Cappello ◽  
Federica Linty ◽  
Roberto Chiarle ◽  
Isabella Sperduti ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Models ◽  
Genetically Engineered ◽  
Early Sign ◽  
Genetically Engineered Mouse Models

scholarly journals Pre-clinical Models of Metastasis in Pancreatic Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Maria Miquel ◽  
Shuman Zhang ◽  
Christian Pilarsky
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Preclinical Models ◽  
Genetically Engineered Mouse Models ◽  
Solid Malignancy ◽  
Clinical Models ◽  
System Tumor ◽  
Molecular Aspects

Pancreatic ductal adenocarcinoma (PDAC) is a hostile solid malignancy coupled with an extremely high mortality rate. Metastatic disease is already found in most patients at the time of diagnosis, resulting in a 5-year survival rate below 5%. Improved comprehension of the mechanisms leading to metastasis is pivotal for the development of new targeted therapies. A key field to be improved are modeling strategies applied in assessing cancer progression, since traditional platforms fail in recapitulating the complexity of PDAC. Consequently, there is a compelling demand for new preclinical models that mirror tumor progression incorporating the pressure of the immune system, tumor microenvironment, as well as molecular aspects of PDAC. We suggest the incorporation of 3D organoids derived from genetically engineered mouse models or patients as promising new tools capable to transform PDAC pre-clinical modeling and access new frontiers in personalized medicine.

scholarly journals A pipeline for rapidly generating genetically engineered mouse models of pancreatic cancer using in vivo CRISPRCas9 mediated somatic recombination

2018 ◽  
Author(s):  
Noboru Ideno ◽  
Hiroshi Yamaguchi ◽  
Takashi Okumara ◽  
Jonathon Huang ◽  
Mitchel J. Brun ◽  
...  
Keyword(s):  
Mouse Models ◽  
Mouse Strain ◽  
Gene Editing ◽  
High Efficiency ◽  
Intraepithelial Neoplasia ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Specific Expression ◽  
Genetically Engineered Mouse Models

ABSTRACTGenetically engineered mouse models (GEMMs) that recapitulate the major genetic drivers in pancreatic ductal adenocarcinoma (PDAC) have provided unprecedented insights into the pathogenesis of this lethal neoplasm. Nonetheless, generating an autochthonous model is an expensive, time consuming and labor intensive process, particularly when tissue specific expression or deletion of compound alleles are involved. In addition, many of the current PDAC GEMMs cause embryonic, pancreas-wide activation or loss of driver alleles, neither of which reflects the cognate human disease scenario. The advent of CRISPR/Cas9 based gene editing can potentially circumvent many of the aforementioned shortcomings of conventional breeding schema, but ensuring the efficiency of gene editing in vivo remains a challenge. Here we have developed a pipeline for generating PDAC GEMMs of complex genotypes with high efficiency using a single “workhorse” mouse strain expressing Cas9 in the adult pancreas under a p48 promoter. Using adeno-associated virus (AAV) mediated delivery of multiplexed guide RNAs (sgRNAs) to the adult murine pancreas of p48-Cre; LSL-Cas9 mice, we confirm our ability to express an oncogenic KrasG12D allele through homology-directed repair (HDR), in conjunction with CRISPR-induced disruption of cooperating alleles (Trp53, Lkb1 and Arid1A). The resulting GEMMs demonstrate a spectrum of precursor lesions (pancreatic intraepithelial neoplasia [PanIN] or Intraductal papillary mucinous neoplasm [IPMN] with eventual progression to PDAC. Next generation sequencing of the resulting murine PDAC confirms HDR of oncogenic KrasG12D allele at the endogenous locus, and insertion deletion (“indel”) and frameshift mutations of targeted tumor suppressor alleles. By using a single “workhorse” mouse strain and optimal AAV serotype for in vivo gene editing with combination of driver alleles, we have created a facile autochthonous platform for interrogation of the PDAC genome.

Cell Type of Pancreatic Ductal Adenocarcinoma Origin: Implications for Prognosis and Clinical Outcomes

2021 ◽  
pp. 1-6
Author(s):  
Shilpa Patil ◽  
Yan Dou ◽  
Janel L. Kopp
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Mouse Models ◽  
Pancreatic Injury ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Cell Of Origin ◽  
Cell Type ◽  
Genetically Engineered Mouse Models ◽  
Cellular Origin ◽  
Ductal Cells

<b><i>Background:</i></b> Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that has no effective early detection method or treatment to date. <b><i>Summary:</i></b> The normal cell type that initiates PDAC, or its cellular origin, is still unknown. To investigate the contribution of distinct normal epithelial cell types to PDAC tumorigenesis, genetically engineered mouse models were used to show that both acinar and ductal cells are capable of giving rise to PDAC. These studies indicated that genetic mutations and pancreatic injury interact differently with each cellular origin to affect their predilection and process for forming PDAC. In this review, we summarize recent findings using various genetically engineered mouse models in the identification and characterization of the PDAC cell of origin. We also discuss potential implications for cellular origin on tumor development, PDAC transcriptional subtype, and disease prognosis of patients. <b><i>Key Message:</i></b> Although it is clear that both ductal and acinar cells have the potential to form PDAC, whether cellular origin can indeed influence patient prognosis and whether knowledge of cellular origin will aid in the diagnosis or treatment of patients in the future will need further study.

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