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SKP2 knockout in Rb1/p53 deficient transgenic mouse models of osteosarcoma induces macrophage infiltration and drives transcription of genes with favorable prognosis in patients

ABSTRACT: SKP2 knockout in Rb1/p53 deficient transgenic mouse models of osteosarcoma induces macrophage infiltration and drives transcription of genes with favorable prognosis in patients

PROVIDER: PRJNA940848 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23698851_1.fastq.gz	Fastqsanger.gz
	SRR23698851_2.fastq.gz	Fastqsanger.gz
	SRR23698852_1.fastq.gz	Fastqsanger.gz
	SRR23698852_2.fastq.gz	Fastqsanger.gz
	SRR23698853_1.fastq.gz	Fastqsanger.gz

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SKP2 knockout in Rb1/p53 deficient transgenic mouse models of osteosarcoma induces macrophage infiltration and drives transcription of genes with favorable prognosis in patients

Project description:To study SKP2 in osteosarcoma, we generated a Skp2 KO line and a Skp2 intact line of transgenic OS mouse models: germline Skp2 knockout (“TKO”: Osx1-Cre;Rb1lox/lox;p53lox/lox;SKP2) versus Skp2 intact (“DKO”: Osx1-Cre;Rb1lox/lox;p53lox/lox). We then performed bulk RNAseq of the SKP2 KO vs SKP2 intact OS.

2023-10-02 | GSE226634 | GEO

SKP2 Knockout in Rb1/p53-Deficient Mouse Models of Osteosarcoma Induces Immune Infiltration and Drives a Transcriptional Program with a Favorable Prognosis.

Project description:Osteosarcoma is an aggressive bone malignancy with a poor prognosis. One putative proto-oncogene in osteosarcoma is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase. We previously demonstrated that Skp2 knockout in murine osteosarcoma improved survival and delayed tumorigenesis. Here, we performed RNA sequencing (RNA-seq) on tumors from a transgenic osteosarcoma mouse model with conditional Trp53 and Rb1 knockouts in the osteoblast lineage ("DKO": Osx1-Cre;Rb1lox/lox;p53lox/lox) and a triple-knockout model with additional Skp2 germline knockout ("TKO": Osx1-Cre;Rb1lox/lox;p53lox/lox;Skp2-/-), followed by qPCR and immunohistochemistry validation. To investigate the clinical implications of our results, we analyzed a human osteosarcoma patient cohort ("NCI-TARGET OS") with RNA-seq and clinical data. We found large differences in gene expression after SKP2 knockout. Surprisingly, we observed increased expression of genes related to immune microenvironment infiltration in TKO tumors, especially the signature genes for macrophages and to a lesser extent, T cells, B cells, and vascular cells. We also uncovered a set of relevant transcription factors that may mediate these changes. In osteosarcoma patient cohorts, high expression of genes upregulated in TKO was correlated with favorable overall survival, which was largely explained by the macrophage gene signatures. This relationship was further supported by our finding that SKP2 expression was negatively correlated with macrophage infiltration in the NCI-TARGET osteosarcoma and the TCGA Sarcoma cohorts. Overall, our findings indicate that SKP2 may mediate immune exclusion from the osteosarcoma tumor microenvironment, suggesting that SKP2 modulation in osteosarcoma may induce antitumor immune activation.

| S-EPMC10842346 | biostudies-literature

SKP2 knockout in Rb1/p53 deficient mouse models of osteosarcoma induces immune infiltration and drives a transcriptional program with a favorable prognosis.

Project description:PurposeOsteosarcoma (OS) is an aggressive bone malignancy with a poor prognosis. One putative proto-oncogene in OS is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase. We previously demonstrated that SKP2 knockout in murine OS improved survival and delayed tumorigenesis. Here we aim to define the SKP2 drives transcriptional program and its clinical implication in OS.Experimental designWe performed RNA-sequencing (RNA-seq) on tumors from a transgenic OS mouse model with conditional Trp53 and Rb1 knockouts in the osteoblast lineage ("DKO": Osx1-Cre;Rb1lox/lox;p53lox/lox) and a triple-knockout model with additional Skp2 germline knockout ("TKO": Osx1-Cre;Rb1lox/lox;p53lox/lox;SKP2-/-). We validated our RNA-seq findings using qPCR and immunohistochemistry. To investigate the clinical implications of our results, we analyzed a human OS patient cohort ("NCI-TARGET OS") with RNA-seq and clinical data.ResultsWe found large differences in gene expression after SKP2 knockout. Strikingly, we observed increased expression of genes related to immune microenvironment infiltration in TKO tumors. We observed significant increases in signature genes for macrophages and to a lesser extent, T cells, B cells and vascular cells. We also uncovered a set of relevant transcription factors that may mediate the changes. In OS patient cohorts, high expression of genes upregulated in TKO was correlated with favorable overall survival, which was largely explained by the macrophage gene signatures. This relationship was further supported by our finding that SKP2 expression was negatively correlated with macrophage infiltration in the NCI-TARGET OS and the TCGA Sarcoma cohort.ConclusionOur findings indicate that SKP2 may mediate immune exclusion from the OS tumor microenvironment, suggesting that SKP2 modulation in OS may induce anti-tumor immune activation.

| S-EPMC10197654 | biostudies-literature

Comprehensive single cell transcriptomics analysis of murine osteosarcoma uncovers Skp2 function in metastasis, genomic instability and immune activation and reveals additional target pathways

Project description:Osteosarcoma (OS) is the most common primary pediatric bone malignancy. One promising new therapeutic target is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase responsible for ubiquitination and proteasome degradation of substrate p27, thus driving cellular proliferation. We have shown previously that knockout of Skp2 in an immunocompetent transgenic mouse model of OS improved survival, drove apoptosis, and induced tumor inflammation. Here, we applied single-cell RNA-sequencing (scRNA-seq) to study primary OS tumors derived from Osx-Cre driven conditional knockout of Rb1 and Trp53. We showed that murine OS models recapitulate the tumor heterogeneity and microenvironment complexity observed in patient tumors. We further compared this model with OS models with functional disruption of Skp2: one with Skp2 knockout and the other with the Skp2-p27 interaction disrupted (resulting in p27 overexpression). We found reduction of T cell exhaustion and upregulation of interferon activation, along with evidence of replicative and endoplasmic reticulum-related stress in the Skp2 disruption models, and showed that interferon induction was correlated with improved survival in OS patients. Additionally, our scRNA-seq analysis uncovered decreased activities of metastasis-related gene signatures in the Skp2-modulated OS, which we validated by observation of a strong reduction in lung metastasis in the Skp2 knockout mice. Finally, we report several potential mechanisms of escape from targeting Skp2 in OS, including upregulation of Myc targets, DNA copy number amplification and overexpression of alternative E3 ligase genes, and potential alternative lineage activation. These mechanistic insights into OS tumor biology and Skp2 function suggest novel targets for new, synergistic therapies, while the data and our comprehensive analysis may serve as a public resource for further big data-driven OS research.

2024-06-28 | GSE262743 | GEO

MDAMB231 transcriptome response to SKP2 knockdown

Project description:The SKP2 was knockdown by siRNAs in MDA-MB231 cells and RNA-Seq was used to define the transcriptome response to SKP2

2020-12-14 | GSE163110 | GEO

SKP2-affinity-purified mass spectrometry analysis.

Project description:This project aims to identify the SKP2 interaction proteins.

2023-01-05 | PXD039225 | Pride

comparison_col0vsskp2-Functional analysis of the SKP2 and CUL4 proteins

Project description:rs04-04_skp2_cul4 - comparison_col0vsskp2 - Antisense and mutants of the SKP2 and CUL4 genes are compared to the Wt in order to identify the genes controlled by those SCF proteins. - Comparison Col0 versus skp2

2012-03-27 | GSE36651 | GEO

comparison_col0vsskp2-Functional analysis of the SKP2 and CUL4 proteins

2012-03-26 | E-GEOD-36651 | biostudies-arrayexpress

Murine hamatopoietic stem cell (HSC): wild type and Skp2 knockout

Project description:Transcriptional profiling of mouse HSC comparing wild type (WT) and Skp2 knockout Collected bone marrow (BM) cells from WT and Skp2 knockout mice, stained with HSC surface markers for FACS. Collected HSC and extracted total RNA then sent out for microarray analysis.

2015-04-02 | E-GEOD-23064 | biostudies-arrayexpress

Murine hamatopoietic stem cell (HSC): wild type and Skp2 knockout

Project description:Transcriptional profiling of mouse HSC comparing wild type (WT) and Skp2 knockout

2015-04-02 | GSE23064 | GEO