An immunogenic model of KRAS-mutant lung cancer for study of targeted therapy and immunotherapy combinations
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ABSTRACT:
PROVIDER: PRJEB53982 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10317206_1.fastq.gz | Fastqsanger.gz | |||
| ERR10317206_2.fastq.gz | Fastqsanger.gz | |||
| ERR10317207_1.fastq.gz | Fastqsanger.gz | |||
| ERR10317207_2.fastq.gz | Fastqsanger.gz | |||
| ERR10317208_1.fastq.gz | Fastqsanger.gz |
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Project description:Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumors with the host immune system are inadequate, in part due to the low tumor mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumor mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumor mutational burden and autochthonous tumors remained refractory to immunotherapy. However, establishing clonal cell lines from these tumors enabled the generation of an immunogenic syngeneic transplantation model of KRAS-mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, antitumor immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C -expressing tumors was markedly potentiated by the adaptive immune system, highlighting the importance of using immunocompetent models for evaluating targeted therapies. Overall, this model provides a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.SignificanceThis study develops a mouse model of immunogenic KRAS-mutant lung cancer to facilitate the investigation of optimal combinations of targeted therapies with immunotherapies.
| S-EPMC7613674 | biostudies-literature
Project description:We found that in KrasG12D-expressing endometrial organoids, Pten knockdown did not confer tumorigenicity, but Cdkn2a knockdown or Trp53 deletion led to the development of carcinosarcoma (CS), a rare, aggressive tumor comprising both carcinoma and sarcoma.To better characterize the pathogenesis of CS from organoids, we conducted a transcriptome analysis.
2021-06-30 | GSE175512 | GEO
Project description:As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic KrasG12D, develops breast tumors. Upon inactivation of KrasG12D, tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of KrasG12D expression and return. KrasG12D-independent tumor cells show a strong mesenchymal profile with active MAPK/ERK signaling. Both KrasG12D-dependent and KrasG12D-independent tumors display a high level of genomic instability, and KrasG12D-independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial–mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic KrasG12D withdrawal in a novel Trp53-/- breast cancer mouse model. To achieve long-lasting responses in the clinic to RAS-fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.
2022-04-04 | GSE174441 | GEO
Project description:Purpose: determine RNA expression differences in an unbiased fashion between UPS tumors derived from LSL-KrasG12D;Trp53-/- (KP) mice, and UPS tumors derived from LSL-KrasG12D;Trp53-/-;Epas1-/- (KPH2) mice. Epas1 encodes HIF-2alpha protein. RNA-seq was performed on KP (n = 4) and KPH2 (n = 4) derived UPS tumors using Illumina HiSeq 2000.
2015-12-31 | E-GEOD-67672 | biostudies-arrayexpress
Project description:Purpose: determine RNA expression differences in an unbiased fashion between UPS tumors derived from LSL-KrasG12D;Trp53-/- (KP) mice, and UPS tumors derived from LSL-KrasG12D;Trp53-/-;Epas1-/- (KPH2) mice. Epas1 encodes HIF-2alpha protein.
2015-12-31 | GSE67672 | GEO
Project description:The experiment is a study of the effects of signal strength in the Ras pathway. In particular, we studied a gain-of-function mutant of Kras, KrasG12D. We generated these mutant mice and performed microarray analyses on RNA extracted from whole skin, comparing KrasG12D mice to wild-type mice, with three replicates of each.
2011-06-03 | E-MTAB-700 | biostudies-arrayexpress
Project description:For organoid preparation, we first treated the following 4 groups of 8-12 week old mice with tamoxifen: 1) CDX2P-CreERT2, Apc flox/+, Kras LSL-G12D/+, Trp53 flox/flox mice (n=2); 2) CDX2P-CreERT2, Apc flox/+, Kras LSL-G12D/+,Trp53 R270H/flox mice (n=3); 3) CDX2P-CreERT2, Apc flox/flox mice (n=3); 4) Wild-type control mice (n=4). The CDX2P-CreERT2 transgene expresses a tamoxifen (TAM)-regulated Cre protein (CreERT2) under control of human CDX2 regulatory sequences, allowing for TAM-inducible targeting of flox alleles in adult mouse terminal ileum, cecum, and colon epithelium. Treating the mice having CDX2P-CreERT2 transgene with tamoxifen permits the Cre recombinase to enter the cell nucleus and recombine the floxed alleles for Apc, Kras, and Trp53, resulting in deletion mutations in Apc and Trp53, and an activating, oncogenic mutation in Kras (G12D mutation). The Trp53 R270H allele carries a constitutive R270H mutation, which is the mouse equivalent of human TP53 R273H mutation. Colon tumors were induced by TAM treatment in all the mice from the first three groups and organoids were derived from the tumors of each mouse. We also derived organoids from the normal colon epithelium in the 4th group of mice as controls. All organoids were generated and propagated using a slightly modified TMDU protocol as described in PMID:20872391. Organoids were cultured for 4 days and then harvested. RNA was purified from the organoids, and targets for Affymetrix arrays were synthesized from the mRNAs. We used Affymetrix Mouse Gene 2.1 ST plate arrays, which hold 41345 probe-sets, but we largely analyzed just those 24562 probe-sets that were mapped to Entrez gene IDs. Raw data was processed with the Robust Multi-array Average algorithm (RMA). Data is log2-transformed transcript abundance estimates. We fit a one-way ANOVA model to the 4 groups of samples. We supply a supplementary excel workbook that holds the same data as the data matrix file for those 24562 probe-sets, but also holds the probe-set annotation at the time we analyzed the data, and some simple statistical calculations, which selects subsets of the probe-sets as differentially expressed between pairs of groups. It also shows data and analysis from a separate experiment of RNA purified directly from 3 groups of mice with genotypes like those of the organoid data except that no group of mice with CDX2P-CreERT2 Apc flox/flox genotype were used. It also joins a statistical summary of differences between 9 human tumors with TP53 missense mutations at codon 273 and 36 tumors with TP53 null mutations assayed with RNA-seq by the TCGA project. A separate supplementary file of the TCGA data is also provided. Consumers should consider obtaining more up-to-date probe-set annotation for the array platform.
2019-06-04 | GSE125261 | GEO
Project description:RNA-Seq analyses of shCtrl (control group) and shPAF (experimental group) KrasG12D; Trp53 knockout (KO)-derived mouse lung cancer cell lines.
2021-04-21 | GSE136571 | GEO
Project description:Ras mutations are commonly observed in Juvenile Myelomonocytic Leukemia (JMML) and Chronic Myelomonocytic Leukemia (CMML). JMML and CMML transform into Acute Myeloid Leukemia (AML) in about 10% and 50% of patients respectively. However, how additional events cooperate with Ras to promote this transformation are largely unknown. We show that absence of the Ubiquitin-Specific-peptidase 22 (USP22), a component of the SAGA chromatin-remodeling complex linked to cancer progression, unexpectedly promotes AML transformation in mice expressing oncogenic KrasG12D/+. USP22 deficiency in KrasG12D/+ mice resulted in shorter survival compared to control mice. This was due to a block in myeloid cell differentiation leading to the generation of AML. This effect was cell autonomous since mice transplanted with USP22-deficient KrasG12D/+ cells developed an aggressive disease and died rapidly. The transcriptome profile of USP22-deficient KrasG12D/+ progenitors resembled leukemic stem cells and was highly correlated with genes associated with poor prognosis in AML. We show that USP22 functions as a PU.1 deubiquitylase by positively regulating its protein stability and promoting the expression of PU.1 target genes. Reconstitution of PU.1 overexpression in USP22-deficient KrasG12D/+ progenitors rescued their differentiation. Our findings uncovered an unexpected role for USP22 in Ras-induced leukemogenesis and provide further insights into the function of USP22 in carcinogenesis.
2018-05-24 | GSE103724 | GEO
Project description:Apc, Kras, and Trp53 mutations
| PRJNA515706 | ENA