MYC oncogene reprograms the local tissue microenvironment during prostate carcinogenesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228945 | GEO | 2023/10/16
REPOSITORIES: GEO
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Project description:MYC oncogene reprograms the local tissue microenvironment during prostate carcinogenesis
| PRJNA952229 | ENA
Project description:Unfolded protein response (UPR) is a central stress response pathway in normal cells that is hijacked by tumor cells for their survival. However, how activation of UPR in cancer cells shapes the tumor microenvironment (TME) remain largely unexplored. Here, we investigated the role of IRE1α-XBP1s on modulation of TME dynamics in prostate cancer (PCa).
2024-08-28 | PXD044287 | Pride
Project description:In this study, we found that OTUD6A is a physiological deubiquitinase for c-Myc in prostate cancer setting and promotes prostatic tumorigenesis through stabilizing c-Myc oncoprotein. Moreover, knockout of Otud6a in mice retarded the prostatic tumorigenesis in Hi-Myc prostate cancer mice model
2022-01-01 | GSE189716 | GEO
Project description:Primary prostate epithelial cell cultures were established from the VENTRAL prostates of FVB mice . Cells were transduced with retroviral expression vectors encoding a single distinct oncogene (c-Myc, Ha-Ras (V-12), v-Src and NeuT, an activating mutant of ErbB2). Individual colonies of oncogene-transduced cells were selected and characterized. These cell lines demonstrate contact-independent growth characteristics in soft agar and in immune competent mice. To further characterize the molecular genetic signaling pathways regulated by specific oncogenes in prostate epithelial cells mRNA was prepared from the oncogene transformed PEC cell lines, 12 samples(each oncogene has 3 lines) and 3 normal prostate epithelial cell controls in good condition.
2013-04-01 | E-GEOD-37428 | biostudies-arrayexpress
Project description:Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet.
2019-08-22 | MTBLS135 | MetaboLights
Project description:The tumor microenvironment (TME) is a complex mixture of tumor cells, immune cells, endothelial cells and fibroblastic stroma cells (FSC). While cancer-associated fibroblasts are generally seen as a tumor-promoting entity, it is conceivable that distinct FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intra-tumoral injection of a recombinant LCMV-based vaccine vector (r3LCMV) expressing the melanocyte differentiation antigen TRP2 results in T cell-dependent eradication of melanomas. Analysis of the TME revealed that viral vector transduction precipitates activation of particular FSC subsets. Using single-cell RNA-seq analysis, we identified a Cxcl13-expressing FSC population with a pronounced immune-stimulatory signature and increased expression of the inflammatory cytokine IL-33. Genetic ablation of Il33 in Cxcl13-Cre+ FSC impeded functionality of intratumoral T cells and consequently tumor control. Thus, reprogramming of distinct FSC subsets in the TME through LCMV-based vectors efficiently promotes tumor eradication by locally sustaining the activity of tumor-specific T cells.
2021-07-03 | E-MTAB-9407 | biostudies-arrayexpress
Project description:Primary prostate epithelial cell cultures were established from the VENTRAL prostates of FVB mice . Cells were transduced with retroviral expression vectors encoding a single distinct oncogene (c-Myc, Ha-Ras (V-12), v-Src and NeuT, an activating mutant of ErbB2). Individual colonies of oncogene-transduced cells were selected and characterized. These cell lines demonstrate contact-independent growth characteristics in soft agar and in immune competent mice. To further characterize the molecular genetic signaling pathways regulated by specific oncogenes in prostate epithelial cells
2013-04-01 | GSE37428 | GEO
Project description:Non-melanoma skin cancer (NMSC) has risen dramatically as a result of chronic exposure to sunlight ultraviolet (UV) radiation, climatic changes and clinical conditions associated with immunosuppression. In spite of considerable progress, our understanding of the mechanisms that control NMSC development and their associated molecular and immunological landscapes is still limited. Here we demonstrated a critical role for galectin-7 (Gal-7), a β-galactoside-binding protein preferentially expressed in skin tissue, during NMSC development. Transgenic mice (Tg46) overexpressing Gal-7 in keratinocytes showed higher number of papillomas compared to WT mice or mice lacking Gal-7 (Lgals7-/-) when subjected to a skin carcinogenesis protocol, in which tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA) and tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were sequentially administered. RNAseq analysis of Tg46 tumor lesions revealed a unique profile compatible with cells of the myelomonocytic lineage infiltrating these tumors, an effect that was substantiated by a higher number of CD11b+Gr1+ cells in tumor-draining lymph nodes. Heightened c-Met activation and Cxcl-1 expression in Tg46 lesions suggested a contribution of this pathway to the recruitment of these cells. Remarkably, Gal-7 bound to the surface of CD11b+Ly6ChiLy6Glo monocytic myeloid cells and enhanced their immunosuppressive activity, as evidenced by increased IL-10 and TGF-β1 secretion, and higher T-cell inhibitory activity. In vivo, carcinogen-treated Lgals7-/- animals adoptively transferred with Gal-7-conditioned monocytic myeloid cells developed higher number of papillomas, whereas depletion of these cells in Tg46-treated mice led to reduction in the number of tumors. Finally, human NMSC biopsies showed increased LGALS7 mRNA and Gal-7 protein expression and displayed transcriptional profiles associated with myeloid programs, accompanied by elevated CXCL1 expression and c-Met activation. Thus, Gal-7 emerges as a critical mediator of skin carcinogenesis and a potential therapeutic target in human NMSC.
| S-EPMC10070502 | biostudies-literature
Project description:The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos). To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA) that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth.
| S-EPMC5448751 | biostudies-literature
Project description:Background & aimsThe leukocyte composition of tumors is heterogeneous, as is the involvement of each leukocyte subset in promoting or restraining tumorigenesis. This heterogeneity reflects the tissue of origin, tumor stage, and the functional state of leukocyte activation, but its biological roots remain poorly understood. Since tumorigenesis is driven by various genetic events, we assessed the role of driver genes in shaping the profiles and the roles of leukocytes in tumorigenesis.MethodsMouse liver tumors were induced by hepatic overexpression of either MYC or the combination of myristoylated AKT and NRAS(V12) oncogenes via hydrodynamic transfection. A comparative, flow cytometry- and histology-based immunophenotyping of liver-infiltrating leukocytes was performed at various stages of liver tumorigenesis. The roles of the most abundant leukocyte subsets in tumorigenesis were addressed by immunodepletion. The contribution of liver injury was assessed by comparing the injury-inducing hydrodynamic transfection model to a model in which MYC is an inducible transgene.ResultsMyristoylated AKT and NRAS(V12) promoted a marked recruitment of CD11b(+)Ly6G(hi)Ly6C(int) neutrophils and CD11b(+)Ly6G(-)Ly6C(hi) monocytes to the liver, but their immunodepletion did not alter tumorigenesis. In contrast, despite minimal invasion by monocytes/neutrophils during MYC-driven tumorigenesis, immunodepletion of these cells reduced MYC tumor burden and extended survival. MYC-driven tumor initiation was augmented specifically by Ly6C+ monocytes and their ability to promote liver injury.ConclusionsOur results demonstrate that leukocyte profiles do not necessarily predict their involvement in tumorigenesis, the functional role of leukocytes can be shaped by oncogenes, and that monocyte-dependent tissue injury selectively cooperates with MYC during tumorigenesis.
| S-EPMC4799762 | biostudies-literature