Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs

Amanda Scherer; Victoria R Stephens; Gavin R McGivney; Wade R Gutierrez; Emily A Laverty; Vickie Knepper-Adrian; Rebecca D Dodd

doi:10.3390/genes11050583

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Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs

Journal article

Open access

Peer reviewed

Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs

Amanda Scherer, Victoria R Stephens, Gavin R McGivney, Wade R Gutierrez, Emily A Laverty, Vickie Knepper-Adrian and Rebecca D Dodd

Genes, Vol.11(5), p.583

05/23/2020

DOI: 10.3390/genes11050583

PMCID: PMC7288323

PMID: 32456131

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https://doi.org/10.3390/genes11050583View

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Abstract

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 gene editing approaches.

Animals

Carcinogenesis - genetics

CD4-Positive T-Lymphocytes - metabolism

CD4-Positive T-Lymphocytes - pathology

CRISPR-Cas Systems - genetics

Disease Models, Animal

Gene Editing

Gene Expression Regulation, Neoplastic - genetics

Genetic Association Studies

Humans

Mice

Mice, Inbred BALB C

Neurofibrosarcoma - diagnosis

Neurofibrosarcoma - genetics

Neurofibrosarcoma - pathology

Tumor Microenvironment - genetics

Details

Title: Subtitle: Distinct Tumor Microenvironments Are a Defining Feature of Strain-Specific CRISPR/Cas9-Induced MPNSTs
Creators: Amanda Scherer - University of Iowa
Victoria R Stephens - University of Iowa
Gavin R McGivney - University of Iowa
Wade R Gutierrez - University of Iowa
Emily A Laverty - University of Iowa
Vickie Knepper-Adrian - University of Iowa
Rebecca D Dodd - University of Iowa
Resource Type: Journal article
Publication Details: Genes, Vol.11(5), p.583
DOI: 10.3390/genes11050583
PMID: 32456131
PMCID: PMC7288323
NLM abbreviation: Genes (Basel)
ISSN: 2073-4425
eISSN: 2073-4425
Grant note: T32 CA078586 / NIH HHS T32 GM067795 / NIGMS NIH HHS P30 CA086862 / NIH HHS R25 GM116686 / NIH HHS T32 GM007337 / NIGMS NIH HHS T32 GM067795 / NIH HHS
Language: English
Date published: 05/23/2020
Academic Unit: Microbiology and Immunology; Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359802902771

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