scholarly journals Amyloid Precursor-Like Protein 2 Expression Increases during Pancreatic Cancer Development and Shortens the Survival of a Spontaneous Mouse Model of Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1535
Author(s):  
Brittany J. Poelaert ◽  
Shelby M. Knoche ◽  
Alaina C. Larson ◽  
Poomy Pandey ◽  
Parthasarathy Seshacharyulu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Biology ◽  
The United States ◽  
Genetically Engineered ◽  
Cancer Development ◽  
Ductal Adenocarcinoma ◽  
Metastatic Progression ◽  
Primary Tumors ◽  
Cancer Initiation

In the United States, pancreatic cancer is a major cause of cancer-related deaths. Although substantial efforts have been made to understand pancreatic cancer biology and improve therapeutic efficacy, patients still face a bleak chance of survival. A greater understanding of pancreatic cancer development and the identification of novel treatment targets are desperately needed. Our analysis of gene expression data from patient samples showed an increase in amyloid precursor-like protein 2 (APLP2) expression within primary tumor epithelium relative to pancreatic intraepithelial neoplasia (PanIN) epithelial cells. Augmented expression of APLP2 in primary tumors compared to adjacent stroma was also observed. Genetically engineered mouse models of spontaneous pancreatic ductal adenocarcinoma were used to investigate APLP2′s role in cancer development. We found that APLP2 expression intensifies significantly during pancreatic cancer initiation and progression in the LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model, as shown by immunohistochemistry analysis. In studies utilizing pancreas-specific heterozygous and homozygous knockout of APLP2 in the KPC mouse model background, we observed significantly prolonged survival and reduced metastatic progression of pancreatic cancer. These results demonstrate the importance of APLP2 in pancreatic cancer initiation and metastasis and indicate that APLP2 should be considered a potential therapeutic target for this disease.

scholarly journals MYC controls metastatic heterogeneity in pancreatic cancer

2021 ◽  
Author(s):  
Ravikanth Maddipati ◽  
Robert J. Norgard ◽  
Timour Baslan ◽  
Komal S. Rathi ◽  
Amy Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Patients ◽  
Ductal Adenocarcinoma ◽  
Tumor Type ◽  
Metastatic Progression ◽  
Primary Tumors ◽  
Functional Differences ◽  
Metastatic Burden

AbstractThe degree of metastatic disease varies widely amongst cancer patients and impacts clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multi-fluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC) – a tumor type where most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor associated macrophages (TAMs), leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC.

scholarly journals An Essential Role forArgonaute 2in EGFR-KRAS Signaling in Pancreatic Cancer Development

2017 ◽  
Author(s):  
Sunita Shankar ◽  
Jean Ching-Yi Tien ◽  
Ronald F. Siebenaler ◽  
Seema Chugh ◽  
Vijaya L. Dommeti ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Specific Inhibitor ◽  
Genetically Engineered ◽  
Cancer Development ◽  
Ductal Adenocarcinoma ◽  
Ras Signaling ◽  
Biphasic Model ◽  
Genetic Ablation ◽  
Pancreatic Cancer Cells ◽  
Genetically Engineered Mouse Model

KRAS and EGFR are known essential mediators of pancreatic cancer development. In addition, KRAS and EGFR have both been shown to interact with and perturb the function of Argonaute 2 (AGO2), a key regulator of RNA-mediated gene silencing. Here, we employed a genetically engineered mouse model of pancreatic cancer to define the effects of conditional loss ofAGO2inKRASG12D-driven pancreatic cancer. Genetic ablation ofAGO2does not interfere with development of the normal pancreas orKRASG12D-driven early precursor pancreatic intraepithelial neoplasia (PanIN) lesions. Remarkably, however,AGO2is required for progression from early to late PanIN lesions, development of pancreatic ductal adenocarcinoma (PDAC), and metastasis.AGO2ablation permits PanIN initiation driven by the EGFR-RAS axis, but rather than progressing to PDAC, these lesions undergo profound oncogene-induced senescence (OIS). Loss ofTrp53(p53) in this model obviates the requirement ofAGO2for PDAC development. In mouse and human pancreatic tissues, increased expression of AGO2 and elevated co-localization with RAS at the plasma membrane is associated with PDAC progression. Furthermore, phosphorylation of AGO2Y393by EGFR disrupts the interaction of wild-type RAS with AGO2 at the membrane, but does not affect the interaction of mutant KRAS with AGO2. ARS-1620, a G12C-specific inhibitor, disrupts the KRASG12C-AGO2 interaction specifically in pancreatic cancer cells harboring this mutant, demonstrating that the oncogenic KRAS-AGO2 interaction can be pharmacologically targeted. Taken together, our study supports a biphasic model of pancreatic cancer development: anAGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and anAGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical to prevent OIS in PanINs and allow progression to PDAC.

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 Models of pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Rayane Dennaoui ◽  
Hridaya Shrestha ◽  
Kay-Uwe Wagner
Keyword(s):  
Pancreatic Cancer ◽  
Developmental Stages ◽  
Biological Significance ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Tumor Type ◽  
Metastatic Progression ◽  
Industrialized Countries ◽  
Research Findings ◽  
Insight Into

AbstractAlthough pancreatic cancer remains to be a leading cause of cancer-related deaths in many industrialized countries, there have been major advances in research over the past two decades that provided a detailed insight into the molecular and developmental processes that govern the genesis of this highly malignant tumor type. There is a continuous need for the development and analysis of preclinical and genetically engineered pancreatic cancer models to study the biological significance of new molecular targets that are identified using various genome-wide approaches and to better understand the mechanisms by which they contribute to pancreatic cancer onset and progression. Following an introduction into the etiology of pancreatic cancer, the molecular subtypes, and key signaling pathways, this review provides an overview of the broad spectrum of models for pancreatic cancer research. In addition to conventional and patient-derived xenografting, this review highlights major milestones in the development of chemical carcinogen-induced and genetically engineered animal models to study pancreatic cancer. Particular emphasis was placed on selected research findings of ligand-controlled tumor models and current efforts to develop genetically engineered strains to gain insight into the biological functions of genes at defined developmental stages during cancer initiation and metastatic progression.

Antitumor activity and immune reponse in CD40 immunotherapy with gemcitabine and nab-paclitaxel in an orthotopic pancreatic cancer mouse model.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 271-271 ◽  
Author(s):  
Despina Siolas ◽  
Jane Cullis ◽  
Antonina Avanzi ◽  
Kate Byrne ◽  
Lawrence P. Leichman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Flow Cytometry ◽  
Immune Response ◽  
Antitumor Activity ◽  
Mouse Model ◽  
Combination Chemotherapy ◽  
Tumor Volume ◽  
Tumor Formation ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma

271 Background: Pancreatic cancer is well known for its aggressive clinical course and resistance to chemotherapy. A Phase I trial of CD40 immunotherapy in combination with gemcitabine demonstrated the combination was safe and achieves tumor responses in patients with pancreatic ductal adenocarcinoma. We investigated the effectiveness of gemcitabine, albumin-bound paclitaxel and CD40 agonist immunotherapy in an orthotopic pancreatic mouse model. Methods: Pancreatic cells obtained from a KrasG12D;Trp53R172H (KPC) genetically engineered mouse were cultivated in cell culture and surgically implanted into the pancreata of immunocompetent syngeneic C57/Bl6 mice allowing for tumor formation in situ. Two weeks after KPC cell implantation, mice were treated with 120 mg/kg gemcitabine and 120 mg/kg nab-paclitaxel by intraperitoneal injection. Forty eight hours after chemotherapy administration, mice were treated with 100 ug of FGK45 CD40 immunotherapy. Mouse tumors and spleens were harvested from euthanized mice ten days after drug treatment. Tumor and spleens were analyzed histologically and by flow cytometry. Results: Mice treated with combination chemotherapy and immunotherapy had a significant reduction in tumor volume in comparison to vehicle treated mice. Combination chemotherapy did not cause a significant decrease in tumor volume. No changes were seen in stromal remodeling using trichrome histological staining. Mice treated with CD40 immunotherapy had an increase in spleen size indicating an immune response. Histological and flow cytometry analysis revealed an increase in CD45+ cells in the tumors of the CD40 immunotherapy treated samples in comparison to chemotherapy alone. Conclusions: CD40 immunotherapy in combination with gemcitabine and albumin-bound paclitaxel has significant antitumor activity in an orthotopic pancreatic cancer mouse model provoking an immune response in the tumors. Future experiments will focus on identifying immune mediators critical for drug efficacy.

Novel murine pancreatic tumor model demonstrates immunotherapeutic control of tumor progression by a Toxoplasma gondii protein

2021 ◽  
Author(s):  
Susan N. Payne ◽  
Philip B. Emmerich ◽  
Nicole M. Davis ◽  
Dustin A. Deming ◽  
Laura J. Knoll
Keyword(s):  
Pancreatic Cancer ◽  
Immune Response ◽  
Dendritic Cells ◽  
Toxoplasma Gondii ◽  
Cancer Biology ◽  
Tumor Volume ◽  
The United States ◽  
Response To Treatment ◽  
Ductal Adenocarcinoma ◽  
Ifn Γ

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer related death in the United States with few effective treatments available and only 10% of those diagnosed surviving 5 years. Although immunotherapeutics are a growing field of study in cancer biology, there has been little progress in their use for the treatment of pancreatic cancer. Pancreatic cancer is considered a nonimmunogenic tumor because the tumor microenvironment does not easily allow for the immune system, even when stimulated, to attack the cancer. Infection with the protozoan parasite Toxoplasma gondii has been shown to enhance the immune response to clear cancer tumors. A subset of T. gondii proteins called Soluble Toxoplasma Antigen (STAg) contains an immunodominant protein called profilin. Both STAg and profilin have been shown to stimulate an immune response that reduces viral, bacterial, and parasitic burdens. Here, we use STAg and profilin to treat pancreatic cancer in a KPC mouse derived allograft murine model. These mice exhibit pancreatic cancer with both Kras and P53 mutations as subcutaneous tumors. Pancreatic cancer tumors in C57BL/6J mice with a wild-type background showed a significant response to treatment with either profilin or STAg; exhibiting a decrease in tumor volume accompanied by an influx in CD4 + and CD8 + T cells in the tumors. Both IFN-γ -/- and Batf3 -/- , which lack conventional dendritic cells, did not show a significant decrease in tumor volume when treated. These results indicate that IFN-γ and dendritic cells may play critical roles in the immune response necessary to treat pancreatic cancer.

scholarly journals Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer

PLoS ONE ◽  
2015 ◽  
Vol 10 (10) ◽  
pp. e0140253 ◽  
Author(s):  
Jamie D. Weyandt ◽  
Benjamin L. Lampson ◽  
Sherry Tang ◽  
Matthew Mastrodomenico ◽  
Diana M. Cardona ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Genetically Engineered ◽  
Wild Type ◽  
Genetically Engineered Mouse Model

Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 21 ◽  
Author(s):  
Huiming Chen ◽  
Junfeng Zhao ◽  
Ningning Jiang ◽  
Zheng Wang ◽  
Chang Liu
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Precancerous Lesions ◽  
Clinical Specimen ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells ◽  
Cancer Initiation

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/β-catenin signaling pathway remains unclear. Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/βcatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/β-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro. Results: Wnt/β-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of β-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro. Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.

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