scholarly journals Genetically Engineered Mouse Models for Human Lung Cancer

10.5772/53721 ◽  
2013 ◽  
Author(s):  
Kazushi Inoue ◽  
Elizabeth Fry ◽  
Dejan Maglic ◽  
Sinan Zhu
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Human Lung ◽  
Genetically Engineered ◽  
Human Lung Cancer ◽  
Genetically Engineered Mouse Models

scholarly journals APOBEC3B expression generates an immunogenic model of Kras mutant lung cancer

2020 ◽  
Author(s):  
Sophie de Carné Trécesson ◽  
Jesse Boumelha ◽  
Emily K. Law ◽  
Pablo Romero-Clavijo ◽  
Edurne Mugarza ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune System ◽  
Mouse Models ◽  
Cytosine Deaminase ◽  
Adaptive Immune System ◽  
Genetically Engineered ◽  
Human Lung Cancer ◽  
Tumour Regression ◽  
Host Immune System ◽  
Mutational Burden

ABSTRACTMutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumour regression but ultimately fail to cure these cancers, leading to intense interest in how best to combine them with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumours with the host immune system are inadequate, in part due to the low tumour mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant Kras-driven lung cancer with an elevated tumour mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This causes an increase in mutational burden in Kras mutant and p53 deleted (KP) tumours and in carcinogen-induced tumours, but these mutations are sub-clonal and do not lead to sensitivity of the autochthonous tumours to immune interventions. However, when clonal cell lines are derived from these tumours they provide an immunogenic syngeneic transplantation lung cancer model that is sensitive to immunotherapy. The ability of a KRAS-G12C inhibitor to cause regression of these tumours is markedly potentiated by the adaptive immune system, providing an opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.

scholarly journals The Oncogenic Potential of a Mutant TP53 Gene Explored in Two Spontaneous Lung Cancer Mice Models

2020 ◽  
Author(s):  
Julian Ramelow ◽  
Christopher Brooks ◽  
Li GaO ◽  
Abeer A Almiman ◽  
Terence M Williams ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Human Lung ◽  
Lung Tumor ◽  
Mutant Gene ◽  
Genetic Mutation ◽  
Tumor Formation ◽  
Human Lung Cancer ◽  
Oncogenic Potential ◽  
Age Related

Abstract BackgroundLung cancer is the number one cancer killer worldwide. A major impediment to progress in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor suppressor gene TP53 are among the most common alterations in human lung cancers.MethodsPreviously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H.ResultsWe found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents.ConclusionsOncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune check point inhibitors or other therapeutic strategies in treatment of lung cancer.

scholarly journals Progress and applications of mouse models for human lung cancer

2010 ◽  
Vol 35 (2) ◽  
pp. 426-443 ◽  
Author(s):  
S. de Seranno ◽  
R. Meuwissen
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Human Lung ◽  
Human Lung Cancer

scholarly journals The oncogenic potential of a mutant TP53 gene explored in two spontaneous lung cancer mice models

2020 ◽  
Author(s):  
Julian Ramelow ◽  
Christopher Brooks ◽  
Li GaO ◽  
Abeer A Almiman ◽  
Terence M Williams ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Human Lung ◽  
Lung Tumor ◽  
Mutant Gene ◽  
Genetic Mutation ◽  
Tumor Formation ◽  
Human Lung Cancer ◽  
Oncogenic Potential ◽  
Age Related

Abstract Background: Lung cancer is the number one cancer killer worldwide. A major impediment to progress in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor suppressor gene TP53 are among the most common alterations in human lung cancers. Methods: Previously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H. Results: We found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents. Conclusions: Oncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune check point inhibitors or other therapeutic strategies in treatment of lung cancer.

Genetically engineered mouse models for lung cancer

2005 ◽  
Vol 2 (1) ◽  
pp. 35-40 ◽  
Author(s):  
Huaiguang Li ◽  
Inseok Kwak ◽  
Francesco J. DeMayo
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models

scholarly journals Mutationally-activated PI3’-kinase-α promotes de-differentiation of lung tumors initiated by the BRAFV600E oncoprotein kinase

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
J Edward van Veen ◽  
Michael Scherzer ◽  
Julia Boshuizen ◽  
Mollee Chu ◽  
Annie Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Human Lung ◽  
Patient Survival ◽  
Genetically Engineered ◽  
Benign Tumors ◽  
Cell Of Origin ◽  
Genetically Engineered Mouse Models ◽  
Human Lung Adenocarcinoma ◽  
Insight Into

Human lung adenocarcinoma exhibits a propensity for de-differentiation, complicating diagnosis and treatment, and predicting poorer patient survival. In genetically engineered mouse models of lung cancer, expression of the BRAFV600E oncoprotein kinase initiates the growth of benign tumors retaining characteristics of their cell of origin, AT2 pneumocytes. Cooperating alterations that activate PI3’-lipid signaling promote progression of BRAFV600E-driven benign tumors to malignant adenocarcinoma. However, the mechanism(s) by which this cooperation occurs remains unclear. To address this, we generated mice carrying a conditional BrafCAT allele in which CRE-mediated recombination leads to co-expression of BRAFV600E and tdTomato. We demonstrate that co-expression of BRAFV600E and PIK3CAH1047R in AT2 pneumocytes leads to rapid cell de-differentiation, without decreased expression of the transcription factors NKX2-1, FOXA1, or FOXA2. Instead, we propose a novel role for PGC1α in maintaining AT2 pneumocyte identity. These findings provide insight into how these pathways may cooperate in the pathogenesis of human lung adenocarcinoma.

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