Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs
The tumor microenvironment plays important roles in cancer biology, but genetic backgrounds of mouse models can complicate interpretation of tumor phenotypes. A deeper understanding of strain-dependent influences on the tumor microenvironment of genetically-identical tumors is critical to exploring...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-05-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/11/5/583 |
| _version_ | 1797567251441778688 |
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| author | Amanda Scherer Victoria R. Stephens Gavin R. McGivney Wade R. Gutierrez Emily A. Laverty Vickie Knepper-Adrian Rebecca D. Dodd |
| author_facet | Amanda Scherer Victoria R. Stephens Gavin R. McGivney Wade R. Gutierrez Emily A. Laverty Vickie Knepper-Adrian Rebecca D. Dodd |
| author_sort | Amanda Scherer |
| collection | DOAJ |
| description | The tumor microenvironment plays important roles in cancer biology, but genetic backgrounds of mouse models can complicate interpretation of tumor phenotypes. A deeper understanding of strain-dependent influences on the tumor microenvironment of genetically-identical tumors is critical to exploring genotype–phenotype relationships, but these interactions can be difficult to identify using traditional Cre/loxP approaches. Here, we use somatic CRISPR/Cas9 tumorigenesis approaches to determine the impact of mouse background on the biology of genetically-identical malignant peripheral nerve sheath tumors (MPNSTs) in four commonly-used inbred strains. To our knowledge, this is the first study to systematically evaluate the impact of host strain on CRISPR/Cas9-generated mouse models. Our data identify multiple strain-dependent phenotypes, including changes in tumor onset and the immune microenvironment. While BALB/c mice develop MPNSTs earlier than other strains, similar tumor onset is observed in C57BL/6, 129X1 and 129/SvJae mice. Indel pattern analysis demonstrates that indel frequency, type and size are similar across all genetic backgrounds. Gene expression and IHC analysis identify multiple strain-dependent differences in CD4+ T cell infiltration and myeloid cell populations, including M2 macrophages and mast cells. These data highlight important strain-specific phenotypes of genomically-matched MPNSTs that have implications for the design of future studies using similar <i>in vivo</i> gene editing approaches. |
| first_indexed | 2024-03-10T19:39:01Z |
| format | Article |
| id | doaj.art-ca21a055105d487a81d0243860a7ba41 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T19:39:01Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-ca21a055105d487a81d0243860a7ba412023-11-20T01:28:45ZengMDPI AGGenes2073-44252020-05-0111558310.3390/genes11050583Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTsAmanda Scherer0Victoria R. Stephens1Gavin R. McGivney2Wade R. Gutierrez3Emily A. Laverty4Vickie Knepper-Adrian5Rebecca D. Dodd6Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Internal Medicine, University of Iowa, Iowa City, IA 52242, USAHolden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USAHolden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USADepartment of Internal Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Internal Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Internal Medicine, University of Iowa, Iowa City, IA 52242, USAThe tumor microenvironment plays important roles in cancer biology, but genetic backgrounds of mouse models can complicate interpretation of tumor phenotypes. A deeper understanding of strain-dependent influences on the tumor microenvironment of genetically-identical tumors is critical to exploring genotype–phenotype relationships, but these interactions can be difficult to identify using traditional Cre/loxP approaches. Here, we use somatic CRISPR/Cas9 tumorigenesis approaches to determine the impact of mouse background on the biology of genetically-identical malignant peripheral nerve sheath tumors (MPNSTs) in four commonly-used inbred strains. To our knowledge, this is the first study to systematically evaluate the impact of host strain on CRISPR/Cas9-generated mouse models. Our data identify multiple strain-dependent phenotypes, including changes in tumor onset and the immune microenvironment. While BALB/c mice develop MPNSTs earlier than other strains, similar tumor onset is observed in C57BL/6, 129X1 and 129/SvJae mice. Indel pattern analysis demonstrates that indel frequency, type and size are similar across all genetic backgrounds. Gene expression and IHC analysis identify multiple strain-dependent differences in CD4+ T cell infiltration and myeloid cell populations, including M2 macrophages and mast cells. These data highlight important strain-specific phenotypes of genomically-matched MPNSTs that have implications for the design of future studies using similar <i>in vivo</i> gene editing approaches.https://www.mdpi.com/2073-4425/11/5/583CRISPR/Cas9MPNSTmouse modelssarcomatumor microenvironment |
| spellingShingle | Amanda Scherer Victoria R. Stephens Gavin R. McGivney Wade R. Gutierrez Emily A. Laverty Vickie Knepper-Adrian Rebecca D. Dodd Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs Genes CRISPR/Cas9 MPNST mouse models sarcoma tumor microenvironment |
| title | Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs |
| title_full | Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs |
| title_fullStr | Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs |
| title_full_unstemmed | Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs |
| title_short | Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs |
| title_sort | distinct tumor microenvironments are a defining feature of strain specific crispr cas9 induced mpnsts |
| topic | CRISPR/Cas9 MPNST mouse models sarcoma tumor microenvironment |
| url | https://www.mdpi.com/2073-4425/11/5/583 |
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