Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA181347 | ENA |
REPOSITORIES: ENA
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Project description:ING proteins play an essential role in the control of a variety of cellular functions whose deregulation is associated with tumor formation and dissemination, such as proliferation, apoptosis, senescence or invasion. Accordingly, loss of function of ING proteins is a frequent event in many types of human tumors. In this report, we have studied the function of ING4, a member of the ING family of tumor suppressors, in the context of normal, non-transformed primary fibroblasts. We show that ING4 negatively regulates cell proliferation in this cell type. The antiproliferative action of ING4 requires its ability to recognize chromatin marks, it is p53-dependent and it is lost in an ING4 cancer-associated mutant. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family. The secretory phenotype regulated by ING4 in primary fibroblasts displays a selective paracrine effect on proliferation, fostering the division of tumor cells, while inhibiting division in primary fibroblasts. Consistently, ING4-expressing fibroblasts promoted tumor growth in vivo in co-injection tumorigenesis assays. Collectively, our results show that ING4 not only can regulate the proliferation of primary non-transformed human fibroblasts, but also orchestrates a secretory phenotype in these cells that promotes tumor cell proliferation in vitro and in vivo. These findings support a critical role for ING4 expression in normal cells in the non-cell autonomous regulation of tumor growth. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family. Two independent retroviral infections were performed in early pasaje IMR-90 fibroblasts with wild-type ING4 wild type and the N214D mutant. All of them were hibridazed by duplicate againts a reference sample from vector-infected cells
2013-04-22 | E-GEOD-42412 | biostudies-arrayexpress
Project description:ING proteins play an essential role in the control of a variety of cellular functions whose deregulation is associated with tumor formation and dissemination, such as proliferation, apoptosis, senescence or invasion. Accordingly, loss of function of ING proteins is a frequent event in many types of human tumors. In this report, we have studied the function of ING4, a member of the ING family of tumor suppressors, in the context of normal, non-transformed primary fibroblasts. We show that ING4 negatively regulates cell proliferation in this cell type. The antiproliferative action of ING4 requires its ability to recognize chromatin marks, it is p53-dependent and it is lost in an ING4 cancer-associated mutant. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family. The secretory phenotype regulated by ING4 in primary fibroblasts displays a selective paracrine effect on proliferation, fostering the division of tumor cells, while inhibiting division in primary fibroblasts. Consistently, ING4-expressing fibroblasts promoted tumor growth in vivo in co-injection tumorigenesis assays. Collectively, our results show that ING4 not only can regulate the proliferation of primary non-transformed human fibroblasts, but also orchestrates a secretory phenotype in these cells that promotes tumor cell proliferation in vitro and in vivo. These findings support a critical role for ING4 expression in normal cells in the non-cell autonomous regulation of tumor growth. Gene expression analysis shows that ING4 regulates the expression and release of soluble factors of the chemokine family.
2013-04-22 | GSE42412 | GEO
Project description:Tumor cells with diverse phenotype and biological behaviors are influenced by stromal cells through secretory factors or direct cell-cell contact. Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia with fibroblasts as the major cell type. Here, we observed enrichment of myofibroblasts in juxta-tumoral position, where tumor cells gain epithelial-mesenchymal transition for invasion, that correlated with worsened prognosis in PDAC patients. Direct cell-cell contacts as forming heterocellular aggregates between fibroblasts and tumor cells were detected in primary pancreatic tumors and circulating tumor microemboli. Mechanistically, the overexpressed ATP1A1 of tumor cells binds to and reorganizes ATP1A1 of fibroblasts inducing calcium oscillations, NF-κB activation, and activin A secretion. Consequentially, either silencing ATP1A1 expression or neutralizing activin A secretion suppresses tumor invasion and colonization. Taken together, these results elucidate the mechanic interplay between tumor cells and the bound fibroblasts in PDAC progression, and provide opportunities for potential therapeutic strategy against tumor metastasis by blocking such interaction.
2022-06-09 | PXD029467 | Pride
Project description:Quiescent (Q) and stress induced premature senescent (SIPS) fibroblasts were treated for the duration of 4 days with growth medium supplemented with a plant extract (1201) from Solidago vigaurea subspecies alpestris. Rna was isolated with Trizol and sent to GATC for next generation sequencing with Ilumina technology. The plant extract proofed to block the negative effects of senescence in human skin fibroblasts in various experiments by delaying the acquisition of a senescent phenotype/favouring a papillary-like phenotype and attenuating the senescence associated secretory phenotype. The RNAseq was performed to understand the underlying molecular mechanism of the observed effects. SIPS was induced by chronic oxidative stress treatment (9 days with 1 h 100 µM H2O2 per day).
2018-03-09 | GSE93535 | GEO
Project description:The DNA damage secretory program (DDSP) provoked by the side effects of genotoxic therapeutics results in senescence associated secretory phenotype (SASP) and fuels advanced pathologies particularly cancer resistance. However, the complete mechanism underlying SASP development in the tumor microenvironment (TME) remains unclear. We treated PSC27, a primary normal human prostate stromal cell line, with two distinct groups of chemotherapeutic drugs that are either genotoxic or not, and determined the key molecules and their associated pathways responsible for development of a typical SASP phenotype under DNA damage conditions.
2018-08-31 | GSE82033 | GEO
Project description:C/EBPβ is an important regulator of oncogene-induced senescence (OIS). Here we show that C/EBPγ, a heterodimeric partner of C/EBPβ whose biological functions are not well understood, inhibits cellular senescence. Cebpg-/- MEFs proliferated poorly, entered senescence prematurely, and expressed a pro-inflammatory gene signature, including elevated levels of senescence-associated secretory phenotype (SASP) genes whose induction by oncogenic stress requires C/EBPβ. The senescence-suppressing activity of C/EBPγ required its ability to heterodimerize with C/EBPβ. Covalently linked C/EBPβ homodimers (β~β) inhibited the proliferation and tumorigenicity of RasV12-transformed NIH3T3 cells, activated SASP gene expression, and recruited the CBP co-activator in a Ras-dependent manner, whereas γ~β heterodimers lacked these capabilities and efficiently rescued proliferation of Cebpg-/- MEFs. C/EBPβ depletion partially restored growth of C/EBPγ-deficient cells, indicating that the increased levels of C/EBPβ homodimers in Cebpg-/- MEFs inhibit proliferation. The proliferative functions of C/EBPγ are not restricted to fibroblasts, as hematopoietic progenitors from Cebpg-/- bone marrow also displayed impaired growth. Furthermore, high CEBPG expression correlated with poorer clinical prognoses in several human cancers, and C/EBPγ depletion decreased proliferation and induced senescence in lung tumor cells. Our findings demonstrate that C/EBPγ neutralizes the cytostatic activity of C/EBPβ through heterodimerization, which prevents senescence and suppresses basal transcription of SASP genes. Mouse embryonic fibroblasts were isolated at E13.5 and propagated. At passage 3 cells were plated with equal density and collected 48 hours later.
2013-06-30 | E-GEOD-47777 | biostudies-arrayexpress
Project description:Cellular senescence, a stable cell growth arrest, can have dual effects in tumors, either suppressing or promoting tumor progression. The Senescence-Associated Secretory Phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, promoting tumor-suppressive over tumor-promoting SASP factors. Here, we identified the Retinoic-Acid-Receptor (RAR) agonist Adapalene as an effective pro-senescence compound in prostate cancer (PCa). The reactivation of the RARs triggers a strong senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of Adapalene and Docetaxel, promotes a tumor-suppressive SASP that activates NK cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors.
2024-02-29 | GSE253331 | GEO
Project description:Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces �SASP-like� inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. This study examines the genome-wide distribution of gH2A.x and H3K4me3 by chIP-seq, using input and whole histone subunit H3 (respectively) as controls for local sonication efficiency bias. Each of the four chIPs has a single replicate each in (i) IMR90 fibroblasts transfected with a scramble control vector, (ii) the same cells subject to oncogene-induced senescence by stimulation of H-Ras V12, and (iii) in OIS cells with a shRNA targeting MLL1. Additionally, gH2A.x and input were sequenced with another replicate in control and OIS cells (both scramble control).
2016-02-23 | E-GEOD-78141 | biostudies-arrayexpress
Project description:The lncRNA MIR31HG regulates the senescence associated secretory phenotype
| PRJNA604779 | ENA
Project description:Evidence is accumulating that senescence drives cure in various murine and human malignancies. We demonstrate that metronomic, repetitive low-dose topotecan treatment leads to tumor cell senescence in vitro and in vivo and long-term cure in a model for the aggressive childhood cancer neuroblastoma. By using the senescence-associated secretory phenotype (SASP) as a discriminator for beneficial versus adverse effects of senescence, we identified topotecan as inducer of a favorable SASP. Senescent tumor cells are growth arrested and act growth inhibitory on co-cultured non-senescent tumor cells. MYCN oncogene amplification and expression, hallmarks of aggressive neuroblastoma, are significantly reduced, supporting an initial transition to a more favorable phenotype. These new aspects of metronomic drug treatment are clinically relevant and might apply to other tumor entities.
2014-12-31 | GSE59529 | GEO