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Sleeping Beauty transposon mutagenesis identified genes involved in colorectal cancer development in the inflammatory microenvironment [wtvsTNF_KrasvsTNF]

ABSTRACT: To identify genes and molecular pathways involved in colorectal cancer (CRC) that developed in an inflammatory microenvironment, we performed Sleeping Beauty (SB) transposon mutagenesis screening in Dextran Sodium Sulfate treated-mice. We have shown that cell cycle-related genes and TGFb pathway-related genes are frequently mutated in inflammation-related tumors. We have demonstrated that TNFa can promote dedifferentiation of colonic epithelial cells via epigenomic reprogramming, and activate both Cdkn2a-p53 signaling and CycD-Cdk4/6, creating advantageous conditions for selecting cells carrying mutations in the Cdkn2a-p53 pathway genes. We have also showed that Cdk4/6 inhibitors are effective against colorectal tumors in an inflammatory microenvironment using the SB mouse model, presenting a potential new therapeutic strategy. Thus, SB screening is not only powerful in identifying genes involved in cancers that develop in specific microenvironments, but also helpful in validating the efficacy of drugs.

ORGANISM(S): Mus musculus

PROVIDER: GSE217169 | GEO | 2023/08/31

REPOSITORIES: GEO

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Sleeping Beauty transposon mutagenesis identified genes involved in colorectal cancer development in the inflammatory microenvironment.

Project description:To identify genes and molecular pathways involved in colorectal cancer (CRC) that developed in an inflammatory microenvironment, we performed Sleeping Beauty (SB) transposon mutagenesis screening in Dextran Sodium Sulfate treated-mice. We have shown that cell cycle-related genes and TGFb pathway-related genes are frequently mutated in inflammation-related tumors. We have demonstrated that TNFa can promote dedifferentiation of colonic epithelial cells via epigenomic reprogramming, and activate both Cdkn2a-p53 signaling and CycD-Cdk4/6, creating advantageous conditions for selecting cells carrying mutations in the Cdkn2a-p53 pathway genes. We have also showed that Cdk4/6 inhibitors are effective against colorectal tumors in an inflammatory microenvironment using the SB mouse model, presenting a potential new therapeutic strategy. Thus, SB screening is not only powerful in identifying genes involved in cancers that develop in specific microenvironments, but also helpful in validating the efficacy of drugs.

2023-08-31 | GSE221326 | GEO

Sleeping Beauty transposon mutagenesis identified genes involved in colorectal cancer development in the inflammatory microenvironment [DSS]

2023-08-31 | GSE217168 | GEO

Sleeping Beauty transposon mutagenesis in mouse intestinal organoids identifies genes involved in tumor progression and metastasis [Atxn1]

Project description:To identify genes important for colorectal cancer (CRC) development and metastasis, we established a new metastatic mouse organoid model using Sleeping Beauty (SB) transposon mutagenesis. Intestinal organoids derived from mice carrying actively mobilizing SB transposons, an activating KrasG12D, and an inactivating ApcΔ716 allele, were transplanted to immunodeficient mice. Analysis of SB insertion sites in tumors identified numerous candidate cancer genes (CCGs) identified previously in intestinal SB screens performed in vivo, in addition to new CCGs, such as Atxn1. To provide functional validation, we knocked out Atxn1 in mouse tumor organoids carrying an activating KrasG12D, and an inactivating ApcΔ716 allele, and transplanted to mice. Tumor development was promoted when these gene were knocked out, demonstrating that these are potent tumor suppressors.

2023-11-27 | GSE248668 | GEO

Sleeping Beauty Expression data from mouse

Project description:We extracted RNA of 39 mouse tissue of various genotypes and performed expression microarrays. Subsequently a screen was conducted using the Sleeping Beauty (SB) transposon to identify breast cancer candidate genes.

2016-01-01 | GSE43263 | GEO

A Sleeping Beauty Forward Genetic Screen Identifies Genes Promoting Osteosarcoma Development and Metastasis

Project description:A Sleeping Beauty (SB) transposon forward genetic screen was performed to identify the genes that promote osteosarcoma (OS) development and metastasis. Mutagenesis induced OS in wild type mice and accelerated it on a Trp53 deficient background. Analysis of tumors demonstrated that Trp53 deficiency is correlated with genomic instability, which was virtually absent in tumors induced by SB mutagenesis alone. Metastases developed in a subset of animals and in nearly all cases were clonal related to primary tumors. Over 200 candidate genes were identified, many of which are altered in human cancers including OS. Signaling pathways enriched for candidate genes were also identified and a subset of these pathways and genes were functionally validated and represent new targets for OS treatment.

2015-04-07 | GSE58770 | GEO

Sleeping Beauty Expression data from mouse

2016-07-03 | E-GEOD-43263 | biostudies-arrayexpress

A Sleeping Beauty Forward Genetic Screen Identifies Genes Promoting Osteosarcoma Development and Metastasis

2015-04-07 | E-GEOD-58770 | biostudies-arrayexpress

CDK4 inhibition diminishes p53 activation by Mdm2-antagonists

Project description:CDK4 inhibitors have reached clinical approval for cancer therapy. In parallel, the p53 antagonist Mdm2 remains an attractive target for anti-cancer therapy, including numerous clinical studies. The genes encoding Mdm2 and CDK4 are frequently co-amplified in human malignancies, most notably in liposarcomas, suggesting their combined targeting for therapy. Here we show, however, that small compounds that inhibit Mdm2 and CDK4 antagonize each other rather than synergize in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon Mdm2 inhibition, and similar results were obtained when depleting Mdm2 and/or CDK4 with siRNA. CDK4 inhibitors also interfered with p53 activity in response to DNA damage. CDK4 inhibition did not reduce p53 binding or histone acetylation to promoters, but rather attenuated the subsequent recruitment of RNA polymerase II. The complexes of p53 and Mdm2, as well as CDK4 and Cyclin D1, physically associated with each other. Upon combined inhibition of Mdm2 and CDK4/6, the interaction of this complex was impaired. Thus, the CDK4-Cyclin D1 complex plays a key role in enabling the transcription of p53 target genes. Taken together, our results raise caution regarding the combination of CDK4 inhibitors with Mdm2 antagonists or conventional DNA-damaging chemotherapeutics in the clinics. Moreover, they suggest a hitherto unknown role for CDK4-cyclin D1 complex in sustaining p53 activity, possibly focusing p53-mediated transcription on actively proliferating cells.

2018-09-20 | GSE113369 | GEO

Identification of genes involved in SHH subgroup medulloblastoma using murine whole-body Sleeping Beauty insertional mutagenesis

Project description:Ptch+/- mice, which are predisposed to SHH subgroup medulloblastoma, were mutagenised using the Sleeping Beauty transposon to identify genes which increase the frequency of medulloblastoma formation. Gene expression in tumours was assessed both to investigate their relationship to human subgroup tumours, and to identify genes where expression was altered by mutagenesis. Total RNA isolated from tumours induced by SB mutagenesis were compared to normal cerebellum, tumours induced witout SB mutagenesis, and tumours from a distinct model of disease (GTML).

2013-07-09 | E-GEOD-43994 | biostudies-arrayexpress

FIRST PHASE I TRIALS OF SLEEPING BEAUTY-MODIFIED CD19-SPECIFIC T CELLS

Project description:Background: T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B-cell malignancies. We provide the first human application of T cells genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. Methods: T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPC) and cytokines. Twenty-six patients with advanced NHL and ALL safely underwent hematopoietic stem-cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n=7) or allogeneic settings (n=19). Results: SB-mediated genetic transposition and stimulation resulted in 2,200-2,500-fold ex vivo genetically modified T-cell expansion, with 84% CAR expression, and without integration hotspots. The 30-month progression-free and overall survivals were 83% and 100%, respectively, following autologous HSCT, and the respective 12-month rates after allogeneic HSCT were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host-disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous and 51 days for allogeneic recipients. Conclusions: CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT, supporting further clinical development of this non-viral gene therapy approach.

2016-06-08 | GSE83076 | GEO

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