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.

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.

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.

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 Preclinical Models of Pancreatic Ductal Adenocarcinoma and Their Utility in Immunotherapy Studies

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 440
Author(s):  
Thao N. D. Pham ◽  
Mario A. Shields ◽  
Christina Spaulding ◽  
Daniel R. Principe ◽  
Bo Li ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Mouse Models ◽  
Ex Vivo ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Preclinical Models ◽  
Dismal Prognosis ◽  
Clinical Benefits ◽  
Combination Regimens

The advent of immunotherapy has transformed the treatment landscape for several human malignancies. Antibodies against immune checkpoints, such as anti-PD-1/PD-L1 and anti-CTLA-4, demonstrate durable clinical benefits in several cancer types. However, checkpoint blockade has failed to elicit effective anti-tumor responses in pancreatic ductal adenocarcinoma (PDAC), which remains one of the most lethal malignancies with a dismal prognosis. As a result, there are significant efforts to identify novel immune-based combination regimens for PDAC, which are typically first tested in preclinical models. Here, we discuss the utility and limitations of syngeneic and genetically-engineered mouse models that are currently available for testing immunotherapy regimens. We also discuss patient-derived xenograft mouse models, human PDAC organoids, and ex vivo slice cultures of human PDAC tumors that can complement murine models for a more comprehensive approach to predict response and resistance to immunotherapy regimens.

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.

Origin of Gliomas

2018 ◽  
Vol 38 (01) ◽  
pp. 005-010 ◽  
Author(s):  
Sevin Turcan ◽  
Daniel Cahill
Keyword(s):  
Mouse Models ◽  
Current Knowledge ◽  
Treatment Options ◽  
Genetically Engineered ◽  
Tumor Evolution ◽  
Screening Methods ◽  
Cell Of Origin ◽  
Genetically Engineered Mouse Models ◽  
Control Tumor Growth ◽  
Control Tumor

Malignant glioma is a common type of brain tumor that remains largely incurable. Although a definitive cell of origin of gliomas remains elusive, numerous population studies, sequencing efforts, and genetically engineered mouse models have contributed to our understanding of the early events that may lead to gliomagenesis. Herein we summarize our current knowledge on the population epidemiology of gliomas, heritable genetic risk factors, the somatic events that contribute to tumor evolution, and mouse models that have shed light on the glioma cell of origin. Future studies will increase our understanding of the sequence of early events within susceptible cells and their niche that trigger the path to malignant transformation. Such knowledge will allow us to design more effective treatment options to control tumor growth or screening methods for early detection.

Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma

Gut ◽  
2018 ◽  
Vol 68 (3) ◽  
pp. 487-498 ◽  
Author(s):  
Alex Y L Lee ◽  
Claire L Dubois ◽  
Karnjit Sarai ◽  
Soheila Zarei ◽  
David F Schaeffer ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Acinar Cells ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
High Grade ◽  
Cell Of Origin ◽  
Ductal Cells ◽  
Tumour Development ◽  
Cellular Context ◽  
The Impact

ObjectivePancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumour thought to arise from ductal cells via pancreatic intraepithelial neoplasia (PanIN) precursor lesions. Modelling of different genetic events in mice suggests both ductal and acinar cells can give rise to PDAC. However, the impact of cellular context alone on tumour development and phenotype is unknown.DesignWe examined the contribution of cellular origin to PDAC development by inducing PDAC-associated mutations, KrasG12D expression and Trp53 loss, specifically in ductal cells (Sox9CreER;KrasLSL-G12D;Trp53flox/flox (‘Duct:KPcKO’)) or acinar cells (Ptf1aCreER;KrasLSL-G12D;Trp53flox/flox (‘Acinar:KPcKO’)) in mice. We then performed a thorough analysis of the resulting histopathological changes.ResultsBoth mouse models developed PDAC, but Duct:KPcKO mice developed PDAC earlier than Acinar:KPcKO mice. Tumour development was more rapid and associated with high-grade murine PanIN (mPanIN) lesions in Duct:KPcKO mice. In contrast, Acinar:KPcKO mice exhibited widespread metaplasia and low-grade as well as high-grade mPanINs with delayed progression to PDAC. Acinar-cell-derived tumours also had a higher prevalence of mucinous glandular features reminiscent of early mPanIN lesions.ConclusionThese findings indicate that ductal cells are primed to form carcinoma in situ that become invasive PDAC in the presence of oncogenic Kras and Trp53 deletion, while acinar cells with the same mutations appear to require a prolonged period of transition or reprogramming to initiate PDAC. Our findings illustrate that PDAC can develop in multiple ways and the cellular context in which mutations are acquired has significant impact on precursor lesion initiation, disease progression and tumour phenotype.

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