Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment
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ABSTRACT:
PROVIDER: PRJNA1160310 | ENA |
REPOSITORIES: ENA
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Project description:Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. Here, we find that genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and anti-tumor immunity via recruitment of cytotoxic T-cells, ultimately impeding tumor progression. Our findings reveal a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.
2024-11-04 | GSE277063 | GEO
Project description:ARF suppression by MYC but not MYCN confers increased malignancy of Group 3 medulloblastoma
| PRJNA578864 | ENA
Project description:Group 3 medulloblastoma (MB) carries the worst prognosis of the four molecular subgroups of MB. MYC amplifications represent the most common genetic alteration in Group 3 MB. By specifically driving MYC in hindbrain cells using a Tet-OFF system, we established a novel murine model of MB (GMYC) that accurately recapitulates human Group 3 MB. GMYC tumours develop with 60-70% penetrance, without p53 mutations, and are monoclonal as revealed by multicolour cell fate tracing. Compared to MYCN-driven Group 3 tumours driven from the same promoter, the ARF suppressor gene was significantly downregulated in GMYC tumours and specifically silenced by methylation in MYC-amplified human MB. While MYCN-driven tumour malignancy was more sensitive to ARF depletion, it dramatically increased the metastatic spread of MYC-driven tumours. Finally, the DNMT inhibitor decitabine could restore ARF levels and suppress MYC-driven tumour growth providing a promising targeting approach for these high-risk tumours.
2022-12-21 | GSE139240 | GEO
Project description:Signal Transducer and Activator of Transcription 3 (STAT3) is considered as an oncogene being constitutively activated in a wide variety of primary human tumours, which often become addicted to its activity. Using primary fibroblasts derived from a knock-in mouse expressing only the constitutively active form STAT3-C as well as STAT3-dependent tumor cell lines MDA-MB468, DU145 and SKBR3, we provide evidence that STAT3 can act as a central regulator of cell metabolism. STAT3C/C MEFs are resistant to apoptosis and senescence and they show reduced mitochondrial activity but activate aerobic glycolysis, as shown by enhanced expression of master regulators of glycolysis such as PDK-1 and HIF-1α, and by increased lactate production, glucose avidity and sensitivity to glycolysis inhibitors. HIF-1α is up-regulated in the STAT3C/C MEFs and is responsible for the glycolytic phenotype. Moreover, inhibition of STAT3 activity in STAT3-addicted tumour cell lines restores mitochondrial activity and down-regulates glycolytic metabolism, preceding the induction of massive apoptosis. Thus, the essential role observed for STAT3 in so many different cancer cell types may be partly explained by its ability to act as a molecular switch of cellular metabolism triggering abnormal cell survival/proliferation. Three biological replicates of MEFs from mice with constitutively active Stat3 are compared to three biological replicates of wild-type MEFs.
2010-11-17 | E-GEOD-21507 | biostudies-arrayexpress
Project description:Signal Transducer and Activator of Transcription 3 (STAT3) is considered as an oncogene being constitutively activated in a wide variety of primary human tumours, which often become addicted to its activity. Using primary fibroblasts derived from a knock-in mouse expressing only the constitutively active form STAT3-C as well as STAT3-dependent tumor cell lines MDA-MB468, DU145 and SKBR3, we provide evidence that STAT3 can act as a central regulator of cell metabolism. STAT3C/C MEFs are resistant to apoptosis and senescence and they show reduced mitochondrial activity but activate aerobic glycolysis, as shown by enhanced expression of master regulators of glycolysis such as PDK-1 and HIF-1α, and by increased lactate production, glucose avidity and sensitivity to glycolysis inhibitors. HIF-1α is up-regulated in the STAT3C/C MEFs and is responsible for the glycolytic phenotype. Moreover, inhibition of STAT3 activity in STAT3-addicted tumour cell lines restores mitochondrial activity and down-regulates glycolytic metabolism, preceding the induction of massive apoptosis. Thus, the essential role observed for STAT3 in so many different cancer cell types may be partly explained by its ability to act as a molecular switch of cellular metabolism triggering abnormal cell survival/proliferation.
2010-11-17 | GSE21507 | GEO
Project description:The Arf GTPase family is involved in a wide range of cellular regulation including membrane trafficking and organelle structure assembly. Here, we have generated a proximity interaction network for the Arf family using the miniTurboID approach combined with TMT-based quantitative mass spectrometry. Our interactome confirmed known interactions and identifies many novel interactors that provide leads for defining Arf pathway cell biological functions.
2022-07-20 | PXD033382 | Pride
Project description:Comparison of gene expression of Ink4a/Arf-/- vs Bmi1-/-;Ink4a/Arf-/- subventricular zone (SVZ) derived mouse neural stem cells (NSC) on Laminin (LM) and Fibronectin (FN) substrates.
2009-02-25 | E-NCMF-22 | biostudies-arrayexpress
Project description:In Arabidopsis and presumably other flowering plant species as well, there are two non-conserved putative ARF GTPases in addition to the eukaryotically conserved ARF1 (class I) and eight ARF guanine-nucleotide exchange factors (ARF-GEFs) that appear to be involved in specific membrane-trafficking pathways. The aim of the study is to analyze which of the ARFs is activated by which ARF-GEF.
2018-11-07 | PXD011594 | Pride
Project description:Loss of function of CDKN2A/B, also known as INK4/ARF [encoding for p16INK4A, p15INK4B, and p14ARF (mouse p19Arf)]), confers susceptibility to cancers, whereas its up-regulation during organismal aging provokes cellular senescence and tissue degenerative disorders. To better understand molecular regulation of the locus, we knocked P2A-mCherry into the C-terminus of p16INK4A, and this construct faithfully recapitulated the endogenous transcription. Using this reporter cell line, we performed a noncoding tiling pooled screening targeting open chromatin regions spanning the approximately 500-kb region in the topological associated domain that includes p16INK4A. In both Cas9- and dCas9-KRAB–mediated screenings, we identified a 42-bp DNA sequence within exon 1β of the ARF gene, as the repressive element controlling p16INK4A expression. Chromatin conformation capture indicated that inactivating this element abolished the physical interaction between p15INK4B and ARF, thereby abolishing p16INK4A repression. This study has revealed a new mechanism of transcriptional regulation of p16INK4A by long-range chromatin interaction.
2019-12-17 | GSE125666 | GEO
Project description:Loss of function of CDKN2A/B, also known as INK4/ARF [encoding for p16INK4A, p15INK4B, and p14ARF (mouse p19Arf)]), confers susceptibility to cancers, whereas its up-regulation during organismal aging provokes cellular senescence and tissue degenerative disorders. To better understand molecular regulation of the locus, we knocked P2A-mCherry into the C-terminus of p16INK4A, and this construct faithfully recapitulated the endogenous transcription. Using this reporter cell line, we performed a noncoding tiling pooled screening targeting open chromatin regions spanning the approximately 500-kb region in the topological associated domain that includes p16INK4A. In both Cas9- and dCas9-KRAB–mediated screenings, we identified a 42-bp DNA sequence within exon 1β of the ARF gene, as the repressive element controlling p16INK4A expression. Chromatin conformation capture indicated that inactivating this element abolished the physical interaction between p15INK4B and ARF, thereby abolishing p16INK4A repression. This study has revealed a new mechanism of transcriptional regulation of p16INK4A by long-range chromatin interaction.
2019-12-17 | GSE125841 | GEO