Characterization of an orthotopic mouse transplant model reveals early changes in the tumor microenvironment of lung cancer
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To understand the cellular and molecular dynamics in the earlystages of lung cancer, we explored a mouse model of orthotopictumor transplant created from the Lewis Lung Carcinoma(LLC) cell line. Employing single-cell RNA sequencing, we analyzedthe cellular landscape during tumor engraftment, focusingparticularly on LLC cells harboring the Kras G12C mutation. This allowed us to identify LLC tumor cells via the detection ofmutant Kras transcripts and observe elevated levels of Myc andmesenchymal gene expression. Moreover, our study revealedsignificant alterations in the lung microenvironment, includingthe activation of tissue remodeling genes in fibroblasts and thedownregulation of MHC class II genes in myeloid subsets. Additionally,T/NK cell subsets displayed more regulatory phenotypes,coupled with reduced proliferation in CD8+ T cells. Collectively,these findings enhance our understanding of lung cancerprogression, particularly in a tumor microenvironment with lowimmunogenicity.
Abstract
To understand the cellular and molecular dynamics in the earlystages of lung cancer, we explored a mouse model of orthotopictumor transplant created from the Lewis Lung Carcinoma(LLC) cell line. Employing single-cell RNA sequencing, we analyzedthe cellular landscape during tumor engraftment, focusingparticularly on LLC cells harboring the Kras G12C mutation. This allowed us to identify LLC tumor cells via the detection ofmutant Kras transcripts and observe elevated levels of Myc andmesenchymal gene expression. Moreover, our study revealedsignificant alterations in the lung microenvironment, includingthe activation of tissue remodeling genes in fibroblasts and thedownregulation of MHC class II genes in myeloid subsets. Additionally,T/NK cell subsets displayed more regulatory phenotypes,coupled with reduced proliferation in CD8+ T cells. Collectively,these findings enhance our understanding of lung cancerprogression, particularly in a tumor microenvironment with lowimmunogenicity.
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