Genetically Engineered Mouse Models of Esophageal Cancer

2021 ◽  
pp. 112757
Author(s):  
Reihaneh Alsadat Mahmoudian ◽  
Moein Farshchian ◽  
Mohammad Reza Abbaszadegan
Keyword(s):  
Esophageal Cancer ◽  
Mouse Models ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models

scholarly journals DIPG-41. DISSECTING THE MECHANISTIC BASIS FOR ACVR1 AND PIK3CA MUTATION CO-OCCURRENCE IN DIFFUSE MIDLINE GLIOMAS USING GENETICALLY ENGINEERED MOUSE MODELS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii295-iii295
Author(s):  
Annette Wu ◽  
Tak Mak ◽  
Jerome Fortin
Keyword(s):  
Mouse Models ◽  
Pik3ca Mutation ◽  
Cell Lineage ◽  
Gene Expression Signature ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Dismal Prognosis ◽  
Human Pathology ◽  
Genes Encoding ◽  
Mechanistic Basis

Abstract Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors with a dismal prognosis. Most of these tumors carry K27M mutations in histone H3-encoding genes, particularly H3F3A and HIST1H3B. In addition, activating mutations in ACVR1 and PIK3CA co-occur in a subset of DMGs. To understand how these lesions drive the development of DMGs, we generated genetically engineered mouse models in which Acvr1G328V, Hist1h3bK27M, and Pik3caH1047R are targeted to the OLIG2-expressing cell lineage. Animals carrying Acvr1G328V and Pik3caH1047R, with (“AHPO”) or without (“APO”) Hist1h3bK27M, developed high-grade diffuse gliomas involving midline and forebrain regions. Neither Acvr1G328V nor Pik3caH1047R drove tumorigenesis by themselves, but Acvr1G328V was sufficient to cause oligodendroglial differentiation arrest, pointing to a role in the earliest stages of gliomas formation. Transcriptomic analyses of AHPO and APO tumors indicated a predominantly proneural and oligodendrocyte precursor-like gene expression signature, consistent with the corresponding human pathology. Genes encoding transcription factors (TFs) with dual roles in controlling glial and neuronal differentiation were upregulated in tumors. Some of these genes were mildly induced by Acvr1G328V alone. Functional experiments using CRISPR/Cas9-mediated gene editing in patient-derived cell lines confirmed a role for some of these TFs in controlling DMG cell fitness. Overall, our results suggest that Pik3caH1047R consolidates Acvr1G328V-induced glial differentiation arrest to drive DMG development and progression.

scholarly journals Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

2016 ◽  
Vol 113 (42) ◽  
pp. E6409-E6417 ◽  
Author(s):  
David G. McFadden ◽  
Katerina Politi ◽  
Arjun Bhutkar ◽  
Frances K. Chen ◽  
Xiaoling Song ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Mouse Models ◽  
Cancer Progression ◽  
Large Scale ◽  
Human Cancer ◽  
Genetically Engineered ◽  
Model Systems ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Genetically Engineered Mouse Models

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

Abstract 215: The Role of Titin in Cardiac Function: Studies in Two Genetically Engineered Mouse Models With Disparate Titin’s Size

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Mei Methawasin ◽  
Kirk R Hutchinson ◽  
John E Smith ◽  
Henk L Granzier
Keyword(s):  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Exercise Capacity ◽  
Mouse Models ◽  
Wheel Running ◽  
Left Ventricular ◽  
Genetically Engineered ◽  
Passive Stiffness ◽  
Genetically Engineered Mouse Models

Titin, a myofilament that acts as a molecular spring in the sarcomere, is considered the main contributor to passive stiffness of cardiomyocytes and is responsible for cardiac diastolic function. Increased titin stiffness is related to diastolic dysfunction and HFpEF (Heart Failure with preserved Ejection Fraction). Alteration in size of titin’s spring region leads to changes in cardiomyocyte and left ventricular (LV) chamber stiffness. We tested the effect of alteration in titin’s size in two genetically engineered mouse models. We investigated the effect of shortening titin’s spring region in a mouse model in which I-band/A-band region of titin’s spring has been deleted (TtnΔIAjxn ), in comparison to the effect of lengthening titin’s spring region in a mouse model deficient in titin splicing factor (Rbm20ΔRRM). Integrative approaches were used from single cardiomyocyte mechanics to pressure-volume analysis and exercise study. Study of skinned LV cardiomyocytes revealed that cellular passive stiffness was inversely related to the size of titin. Cellular passive stiffness was increased in TtnΔIAjxn homozygous (-/-) (~ 110 % higher than wildtype (WT)) and was reduced in a graded manner in Rbm20ΔRRM heterozygous (+/-) and -/- cardiomyocytes (~61% and ~87% less than WT). This effect was carried through at the LV chamber level which could be demonstrated in pressure volume (PV) analysis as an increased end-diastolic pressure-volume relationship (EDPVR) in TtnΔIAjxn -/- (~110% higher than WT’s hearts) and reduced EDPVR in Rbm20ΔRRM +/- and -/- (~57% and ~48% less than WT’s hearts). Free-wheel running studies revealed a running deficiency in TtnΔIAjxn -/- mice but an increase in exercise capacity in Rbm20ΔRRM +/– mice. Conclusions: Functional studies from the cellular to in-vivo LV chamber levels showed that mice with shortening of titin’s spring region had increased LV stiffness, diastolic dysfunction and reduced exercise capacity, while mice with lengthening titin’s spring region had compliant LV and increased exercise capacity. Thus, our work supports titin’s important roles in LV diastolic function and suggests that modification of the size of titin’s spring region could be a potential therapeutic strategy for HFpEF.

scholarly journals The rise of genetically engineered mouse models of pancreatitis: A review of literature

2018 ◽  
Vol 9 (1) ◽  
pp. 103-114 ◽  
Author(s):  
Troy L. Merry ◽  
Maxim S. Petrov
Keyword(s):  
Mouse Models ◽  
High Frequency ◽  
Genetically Engineered ◽  
Current Understanding ◽  
Review Of Literature ◽  
Local Inflammation ◽  
Cellular Mechanisms ◽  
Genetically Engineered Mouse Models

AbstractPancreatitis is increasingly recognized as not merely a local inflammation of the pancreas but also a disease with high frequency of systemic sequelae. Current understanding of the cellular mechanisms that trigger it and affect the development of sequelae are limited. Genetically engineered mouse models can be a useful tool to study the pathophysiology of pancreatitis. This article gives an overview of the genetically engineered mouse models that spontaneously develop pancreatitis and discusses those that most closely replicate different pancreatitis hallmarks observed in humans.

scholarly journals Rapid Validation of Cancer Genes and Drug Targets in Genetically Engineered Mouse Models of Cancer

2013 ◽  
Vol 24 ◽  
pp. i7
Author(s):  
I.J. Huijbers ◽  
R. Bin Ali ◽  
C. Pritchard ◽  
M. Cozijnsen ◽  
N. Proost ◽  
...  
Keyword(s):  
Mouse Models ◽  
Drug Targets ◽  
Genetically Engineered ◽  
Cancer Genes ◽  
Genetically Engineered Mouse Models ◽  
Mouse Models Of Cancer
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