Project description:Comparison of gene expression of mouse lung adenocarcinoma-associated macrophages isolated from C57BL/6 mice injected with Kras-CL and Kras IKKa low cells
Project description:Comparison of gene expression of mouse lung adenocarcinoma-associated CD4 cells isolated from C57BL/6 mice injected with Kras-CL and Kras IKKa low cells
Project description:To identify the mechanisms driving resistance upon KrasG12V ablation, we established lung cancer cell lines that carried loxP sequences flanking the exon 1 of Kras containing the G12V mutation (Kras +/loxG12Vlox), and lacked Trp53 alleles (Trp53 -/-). Tumor cells were infected with Adeno-Cre particles to excise the floxed sequences and individual cells that survived were expanded for further analysis.
Project description:This SuperSeries is composed of the following subset Series: GSE32415: Mouse lung tumor tissue: Dnmt3a KO vs. Dnmt3a WT GSE32484: DNA methylation of dnmt3a deficient Kras lung tumors and dnmt3a wt Kras lung tumors Refer to individual Series
Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample
Project description:We have shown that Gprc5a-/- mice form Kras-mutant lung tumors spontaneously which is accelerated by tobacco carcinogen (NNK) exposure. We found in these mice that Lcn2 was distinctively up-regulated along the spectrum of Kras-mutant lung cancer development. To understand the role of Lcn2 in lung cancer pathogenesis, we generated Gprc5a-/-/Lcn2-/- mice and found that these animals have increased lung tumor devleopment following NNK compared to Gprc5a-/- animals with intact Lcn2. To understand these effects, we performed RNA-sequencing (RNA-Seq) of lung tissues from Gprc5a-/-/Lcn2-/- and Gprc5a-/- mice at baseline (prior to NNK exposure) and of tumor-bearing lungs from both groups at seven months post-NNK exposure.
Project description:Recent data suggests that repression of the Type II TGF-B Receptor (Tgfr2) repression in human lung adenocarcinoma is important for progression from noninvasive to invasive adenocarcinoma. To test this hypothesis in a animal model of non-invasive lung cancer, we generated an inducible, lung specific Tgfbr2 knockout model in the oncogenic Kras mouse. LSL-KrasG12D positive mice were simultaneously backcrossed to C57/Bl6 mice and to the Tgfbr2 flox/flox mice. To induce tumors, 100 ul of saline containing 3x10e10 particles of an adenovirus containing the Cre recombinase (Ad.Cre) was administered to each LSL-KrasG12D mouse intra-nasally. We evaluated the tumor microenvironment response to Tgfbr2 deficient tumor cells. We compared lung tumor cell and stromal cell transcriptional profiles from five-week KrasTgfbr2 -/- and nine-week KrasTgfbr2 WT mice. We used mice at these time points to allow comparison of the stromal compartment of similarly advanced tumors.