Ontology highlight
ABSTRACT:
PROVIDER: PRJNA978792 | ENA |
REPOSITORIES: ENA
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Project description:Repressed Blautia-acetate immunological axis underlies chronic stress promoted breast cancer progression
| PRJNA970310 | ENA
Project description:Fermenting microbial communities generate hydrogen: its removal through production of acetate, methane, or hydrogen sulfide modulates the efficiency of energy extraction from available nutrients in many ecosystems. We noted that pathway components for acetogenesis are more abundantly and consistently represented in the gut microbiomes of monozygotic twins and their mothers than components for methanogenesis or sulfate reduction, and subsequently analyzed the metabolic potential of two sequenced human gut acetogens, Blautia hydrogenotrophica and Marvinbryantia formatexigens in vitro and in the intestines of gnotobiotic mice harboring a prominent saccharolytic bacterium. To do so, we developed a generally applicable method for multiplex sequencing of expressed microbial mRNAs, and together with mass spectrometry of metabolites, show that these organisms have distinct patterns of substrate utilization. B. hydrogenotrophica targets aliphatic and aromatic amino acids. It increases the efficiency of fermentation by consuming reducing equivalents, thereby maintaining a high NAD+/NADH ratio and boosting acetate production. In contrast, M. formatexigens consumes oligosaccharides, does not impact the redox state of the gut, and boosts the yield of succinate. These findings have strategic implications for those who wish to manipulate the hydrogen economy of gut microbial communities in ways that modulate energy harvest. 119 Samples consisting of Bacteroides thetaiotaomicron, Marvinbryantia formatexigens, and Blautia hydrogenotrophica cecal and fecal samples. Please see the individual Sample descriptions for more information.
2010-05-21 | E-GEOD-21906 | biostudies-arrayexpress
Project description:Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide- and glycan- motif and achieve cell-type selectivity via antigen-driven cell surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in murine models of breast cancer progression. This work establishes a blueprint for the development of biologics that degrade specific glycoproteins on target cells.
2023-07-21 | PXD042243 | Pride
Project description:The ability of tumor cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. However, the signaling and nutritional potential of the stromal cell-secreted metabolites remains poorly understood. We identified a novel metabolic crosstalk between cancer associated fibroblasts (CAFs) and pancreatic cancer cells. We demonstrate that pancreatic CAFs regulate tumor cell metabolism through the secretion of acetate, which can be blocked by silencing ACLY in CAFs. Cancer cells present a unique dependence on CAF-derived acetate under acidosis. We further show that ACSS2 channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in the acidic microenvironment. Comparative H3K27ac ChIP-Seq and RNA-Seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We observed novel acetate/ACSS2-mediated acetylation of SP1 at lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished tumor burden in mouse models. Increased SAT1-mediated production of N1-acetylspermidine correlated with disease progression in the spontaneous tumor progression model and poor survival in cancer patients. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.
2023-10-20 | MSV000093165 | MassIVE
Project description:Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD) but neuronal cultures are confounded by cellular heterogeneity. By applying high-resolution single cell transcriptomic analyses to Parkinson’s iPSC-derived dopamine neurons carrying the GBA-N370S risk variant, we exploited intra-culture cellular heterogeneity to identify a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Analysis of genes differentially-expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with compounds known to modulate HDAC4 activity upregulated genes early in the DE axis, and corrected Parkinson’s-related cellular phenotypes. Our study demonstrates how single cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.
2018-10-17 | E-MTAB-7303 | biostudies-arrayexpress
Project description:The erythropoietin (EPO) hormone induces red blood cell production and its recombinant form is the most prescribed drug for the treatment of anemia, including that arising in cancer patients. Based on randomized trials showing that EPO administration to cancer patients result in a decreased survival, we investigated the impact of EPO modulation on tumorigenesis. Using genetically engineered mouse models of breast cancer we found that EPO promoted tumorigenesis by activating JAK/STAT signaling specifically in breast tumor initiating cells (TICs) and promoting their self-renewal. Moreover, we define an active role for endogenous EPO in breast cancer progression and breast TIC self-renewal and demonstrate a potential application of EPO pathway inhibition in breast cancer therapy. reference x sample
2014-05-31 | E-GEOD-51433 | biostudies-arrayexpress
Project description:NSC 59687 (oxyphenisatin acetate) is a novel anti-cancer agent with selectivity for breast and ovarian cell lines To elucidate the transcripts differentially regulated following treatment with Oxyphenisatin acetate (NSC 59687)
2013-03-13 | GSE45046 | GEO
Project description:Breast cancer is the most common and a lethal form of cancer diagnosed in women worldwide. Although, effective treatment options for primary tumors are available, the majority of breast cancer-related deaths is caused by invasion of cells from primary tumor results in metastatic progression. Here we used a phopshoproteomic analysis to identify new targets of pro-invasive LIM kinase 2 (LIMK2) in invasive breast cancer cell lines. We show that Serine Arginine protein kinase 1 (SRPK1) is phosphorylated and activated by LIMK2 and LIMK2-SRPK1 signaling axis mediate the invasive behavior of breast cancer cells.
2020-08-31 | PXD008246 | Pride
Project description:Triple negative breast cancer (TNBC) is one of the most lethal breast cancer subtypes. Due to a lack of effective therapeutic targets, chemotherapy is still the main medical treatment for TNBC patients. Thus, it is important and necessary to identify novel therapeutic targets for TNBC. Recent genomic studies implicated the hyper-activation of Hippo/YAP signaling in TNBC, manifesting its critical roles in TNBC carcinogenesis and cancer progression. RBCK1 was firstly identified as an important component for linear ubiquitin assembly complex (LUBAC) and facilitates NFKB signaling in immune response. Further studies showed RBCK1 also facilitated luminal type breast cancer growth and endocrine resistance via trans-activation estrogen receptor alpha. Interestingly, our data revealed an opposite function for RBCK1 in TNBC progression. RBCK1 over-expression inhibited TNBC cell progression in vitro and in vivo, while RBCK1depletion promoted TNBC cell invasion. The whole genomic expression profiling showed that RBCK1 depletion activated Hippo/YAP axis. RBCK1 depletion increased YAP protein level and Hippo target gene expression in TNBC. The molecular biology studies showed that RBCK1 could associate with YAP protein and enhance YAP protein stability via promoting YAP K48-linked poly-ubiquitination at several YAP lysine sites (K76, K204 and K321). Our study revealed the multi-faced RBCK1 function in different subtypes of breast cancer patients and a promising therapeutic target for TNBC treatment.
2022-02-05 | GSE195712 | GEO