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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE217170 | 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 [wtvsTNF_KrasvsTNF]

2023-08-31 | GSE217169 | 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 identified genes and pathways involved in inflammation-associated colon tumor development.

Project description:Chronic inflammation promotes development and progression of colorectal cancer (CRC). To comprehensively understand the molecular mechanisms underlying the development and progression of inflamed CRC, we perform in vivo screening and identify 142 genes that are frequently mutated in inflammation-associated colon tumors. These genes include senescence and TGFβ-activin signaling genes. We find that TNFα can induce stemness and activate senescence signaling by enhancing cell plasticity in colonic epithelial cells, which could act as a selective pressure to mutate senescence-related genes in inflammation-associated colonic tumors. Furthermore, we show the efficacy of the Cdk4/6 inhibitor in vivo for inflammation-associated colonic tumors. Finally, we functionally validate that Arhgap5 and Mecom are tumor suppressor genes, providing possible therapeutic targets for CRC. Thus, we demonstrate the importance of the inactivation of senescence pathways in CRC development and progression in an inflammatory microenvironment, which can help progress toward precision medicine.

| S-EPMC10579371 | biostudies-literature

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

Project description:Sleeping Beauty transposon mutagenesis identified genes involved in colorectal cancer development in the inflammatory microenvironment

| PRJNA897840 | ENA

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

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

| PRJNA913906 | ENA

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

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

| PRJNA897839 | ENA

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

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

| PRJNA897838 | ENA

Sleeping Beauty transposon mutagenesis identifies genes that cooperate with mutant Smad4 in gastric cancer development.

Project description:Mutations in SMAD4 predispose to the development of gastrointestinal cancer, which is the third leading cause of cancer-related deaths. To identify genes driving gastric cancer (GC) development, we performed a Sleeping Beauty (SB) transposon mutagenesis screen in the stomach of Smad4(+/-) mutant mice. This screen identified 59 candidate GC trunk drivers and a much larger number of candidate GC progression genes. Strikingly, 22 SB-identified trunk drivers are known or candidate cancer genes, whereas four SB-identified trunk drivers, including PTEN, SMAD4, RNF43, and NF1, are known human GC trunk drivers. Similar to human GC, pathway analyses identified WNT, TGF-?, and PI3K-PTEN signaling, ubiquitin-mediated proteolysis, adherens junctions, and RNA degradation in addition to genes involved in chromatin modification and organization as highly deregulated pathways in GC. Comparative oncogenomic filtering of the complete list of SB-identified genes showed that they are highly enriched for genes mutated in human GC and identified many candidate human GC genes. Finally, by comparing our complete list of SB-identified genes against the list of mutated genes identified in five large-scale human GC sequencing studies, we identified LDL receptor-related protein 1B (LRP1B) as a previously unidentified human candidate GC tumor suppressor gene. In LRP1B, 129 mutations were found in 462 human GC samples sequenced, and LRP1B is one of the top 10 most deleted genes identified in a panel of 3,312 human cancers. SB mutagenesis has, thus, helped to catalog the cooperative molecular mechanisms driving SMAD4-induced GC growth and discover genes with potential clinical importance in human GC.

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Insertional mutagenesis using the Sleeping Beauty transposon system identifies drivers of erythroleukemia in mice.

Project description:Insertional mutagenesis is a powerful means of identifying cancer drivers in animal models. We used the Sleeping Beauty (SB) transposon/transposase system to identify activated oncogenes in hematologic cancers in wild-type mice and mice that express a stabilized cyclin E protein (termed cyclin ET74AT393A). Cyclin E governs cell division and is misregulated in human cancers. Cyclin ET74AT393A mice develop ineffective erythropoiesis that resembles early-stage human myelodysplastic syndrome, and we sought to identify oncogenes that might cooperate with cyclin E hyperactivity in leukemogenesis. SB activation in hematopoietic precursors caused T-cell leukemia/lymphomas (T-ALL) and pure red blood cell erythroleukemias (EL). Analysis of >12,000 SB integration sites revealed markedly different oncogene activations in EL and T-ALL: Notch1 and Ikaros were most common in T-ALL, whereas ETS transcription factors (Erg and Ets1) were targeted in most ELs. Cyclin E status did not impact leukemogenesis or oncogene activations. Whereas most SB insertions were lost during culture of EL cell lines, Erg insertions were retained, indicating Erg's key role in these neoplasms. Surprisingly, cyclin ET74AT393A conferred growth factor independence and altered Erg-dependent differentiation in EL cell lines. These studies provide new molecular insights into erythroid leukemia and suggest potential therapeutic targets for human leukemia.

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