HDAC and NFκB antagonists synergistically inhibit growth and metastatic dissemination of MYC-driven medulloblastoma
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PROVIDER: PRJNA509766 | ENA |
REPOSITORIES: ENA
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Project description:Aberrant oncogenic activation of MYC drives tumorigenesis in the most aggressive subset of medulloblastoma, the most common malignant brain tumor in childhood. Metastatic dissemination at diagnosis and at recurrence is commonly observed in MYC-driven medulloblastomas. Since these tumors display remarkable resistance to standard multimodal therapeutic approaches, epigenetic modulators commonly altered in these tumors are highly promising targets for novel therapeutic approaches. Here, we report on a cross-entity, high-throughput epigenetic drug screen to evaluate therapeutic vulnerabilities in the most common malignant primary brain tumors. Specifically, we performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), medulloblastoma (n=14), and glioblastoma (n=14). This unbiased approach revealed preferential activity of HDACi in MYC-driven medulloblastoma. Importantly, the class I selective HDACi CI-994 showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven medulloblastoma, with little to no activity in non-MYC-driven medulloblastoma, AT/RT, and glioblastoma in vitro. Notably, CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven medulloblastoma. Furthermore, synergistic drug screening and RNA sequencing revealed NFκB pathway induction as a mechanism of resistance to CI-994 treatment. Taken together, our findings identified MYC pathway activation as a predictive biomarker for epigenetic treatment intervention in high-risk medulloblastoma and provide a preclinical rationale for further exploration of CI-994 combined with NFκB pathway inhibitors in the treatment of MYC-driven medulloblastoma.
2019-12-13 | GSE123760 | GEO
Project description: Not available
| S-EPMC4794752 | biostudies-literature
Project description:Photoreceptor degeneration is the central event leading to visual impairment or blindness in most retinal diseases. However, the discovery of safe and effective therapeutic strategies conferring photoreceptor protection remains challenging. A systems pharmacology approach, synergistically targeting distinct cellular pathways could provide an effective strategy for evaluating, preventing or treating retinal dystrophies. Here this concept was investigated using a mouse model of light-induced retinal degeneration. We show that a combination of FDA-approved drugs acting on different G protein-coupled receptors in a synergistic manner could protect retinas against light-induced degeneration when each drug in the combination treatment was administered at a sub-therapeutic dose. Furthermore, transcriptome analyses demonstrated that such combined treatments also preserved patterns of retinal gene expression more characteristic of the normal retina than did single therapies at higher doses. The current study thus supports a new systems pharmacology approach that may extend to other complex neurodegenerative disorders in addition to retinal diseases.
2016-11-15 | GSE79061 | GEO
Project description:Gonadotrophin-releasing hormone (GnRH) significantly inhibits proliferation of a proportion of cancer cell lines by activating GnRH receptor-G protein signaling. Therefore, manipulation of GnRH receptor signaling may have an under-utilized role in treating certain breast and ovarian cancers. However, the precise signaling pathways necessary for the effect and the features of cellular responses remain poorly defined. We used transcriptomic and proteomic profiling approaches to characterize the effects of GnRH receptor activation in sensitive cells (HEK293-GnRHR, SCL60) in in vitro and in vivo settings, compared to unresponsive HEK293. Analyses of gene expression demonstrated a dynamic SCL60 response to the GnRH super-agonist Triptorelin. Early and mid-phase changes (0.5-1.0 h) comprised mainly transcription factors. Later changes (8-24 h) included a GnRH target gene, CGA, and up or down-regulation of transcripts encoding signaling and cell division machinery. Pathway analysis exposed identified altered mitogen-activated protein kinase and cell cycle pathways, consistent with occurrence of G2/M arrest and apoptosis. NFκB pathway gene transcripts were differentially expressed between control and Triptorelin-treated SCL60 cultures. Reverse phase protein and phospho-proteomic array analyses profiled responses in cultured cells and SCL60 xenografts in vivo during Triptorelin anti-proliferation. Increased phosphorylated NFκB (p65) occurred in SCL60 in vitro, and p-NFκB and IκBε were higher in treated xenografts than controls after 4 days Triptorelin. NFκB inhibition enhanced the anti-proliferative effect of Triptorelin in SCL60 cultures. This study reveals details of pathways interacting with intense GnRH receptor signaling, identifies potential anti-proliferative target genes and implicates the NFκB survival pathway as a node for enhancing GnRH agonist-induced anti-proliferation. 55 samples: 35 SCL60 (15 Control, 20 Treated), 20 HEK293 (12 Control, 8 Treated). Samples collected after 0, 0.5, 1, 2, 8 or 24h after treatment with Triptorelin (100nM) or vehicle control (20% Propylene Glycol solution). SCL60 cells are HEK293 cells stably transfected with a high level of functional rat GnRHR.
2012-12-21 | E-GEOD-27467 | biostudies-arrayexpress
Project description:Aging changes global transcriptome including protein-coding and noncoding RNAs. Whether aging dependent lncRNAs undergo conserved regulation and function still remain unknown. We report aging dependent lncRNAs carry signature of evolutionary constraint and significantly enriched for targets of transcription factors and RNA binding proteins. Aging dependent lncRNAs is conservatively under NFκB pathway regulation. CRISPR screening for NFκB pathway found that aging dependent lncRNAs also extensively regulate NFκB pathway. The human LINC02085 is an evolutionary conserved lncRNA that can be traced to 29Mya before human. LINC02085 is induced during aging, inflammation and senescence through NFκB pathway. Reciprocally, LINC02085 directly regulates NFKBIZ in cis within same topological associated domain (TAD). LINC02085 binds to enhancer of NFKBIZ and recruits RELA to the NFKBIZ promoters and participates phase separation. These findings reveal that aging dependent lncRNAs are previously under-appreciated contributors to the evolutionary conservation and regulation of NFκB pathway.
2021-03-08 | GSE167510 | GEO
Project description:Aging changes global transcriptome including protein-coding and noncoding RNAs. Whether aging dependent lncRNAs undergo conserved regulation and function still remain unknown. We report aging dependent lncRNAs carry signature of evolutionary constraint and significantly enriched for targets of transcription factors and RNA binding proteins. Aging dependent lncRNAs is conservatively under NFκB pathway regulation. CRISPR screening for NFκB pathway found that aging dependent lncRNAs also extensively regulate NFκB pathway. The human NFKBMARL-1 is an evolutionary conserved lncRNA that can be traced to 29Mya before human. NFKBMARL-1 is induced during aging, inflammation and senescence through NFκB pathway. Reciprocally, NFKBMARL-1 directly regulates NFKBIZ in cis within same topological associated domain (TAD). NFKBMARL-1 binds to enhancer of NFKBIZ and recruits RELA to the NFKBIZ promoters and participates phase separation. These findings reveal that aging dependent lncRNAs are previously under-appreciated contributors to the evolutionary conservation and regulation of NFκB pathway.
2021-03-08 | GSE167507 | GEO
Project description:Aging changes global transcriptome including protein-coding and noncoding RNAs. Whether aging dependent lncRNAs undergo conserved regulation and function still remain unknown. We report aging dependent lncRNAs carry signature of evolutionary constraint and significantly enriched for targets of transcription factors and RNA binding proteins. Aging dependent lncRNAs is conservatively under NFκB pathway regulation. CRISPR screening for NFκB pathway found that aging dependent lncRNAs also extensively regulate NFκB pathway. The human NFKBMARL-1 is an evolutionary conserved lncRNA that can be traced to 29Mya before human. NFKBMARL-1 is induced during aging, inflammation and senescence through NFκB pathway. Reciprocally, NFKBMARL-1 directly regulates NFKBIZ in cis within same topological associated domain (TAD). NFKBMARL-1 binds to enhancer of NFKBIZ and recruits RELA to the NFKBIZ promoters and participates phase separation. These findings reveal that aging dependent lncRNAs are previously under-appreciated contributors to the evolutionary conservation and regulation of NFκB pathway.
2021-03-08 | GSE167504 | GEO
Project description:The epigenome defines the cell type, but also possesses plasticity to tune gene expression in the context of extracellular cues. This tuning is evident in immune sentinel cells such as macrophages, which respond to pathogens and cytokines with phenotypic shifts driven by epigenomic reprogramming. Recent studies indicate that this reprogramming arises from the activity of transcription factors including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB binds not only to available enhancers but may also produce de novo enhancers in previously silent areas of the genome. Here, we show that NFκB reprograms the macrophage epigenome in a stimulus-specific manner, in response only to a subset of pathogen-derived stimuli. The basis for these surprising differences lies in the stimulus-specific temporal dynamics of NFκB activity. In response to different stimuli, NFκB enters the nucleus with variable speed, amplitude, and duration, and may oscillate between the nucleus and cytoplasm. These dynamical features combine to specify the identity and dose of a given stimulus. We demonstrate through live cell imaging, mathematical modeling, and genetic perturbations that NFκB promotes open chromatin and formation of de novo enhancers most strongly when its dynamics are non-oscillatory. These de novo enhancers result in the activation of additional response genes. We propose a mechanistic paradigm in which the temporal dynamics of transcription factors are a key determinant of their capacity to control epigenomic reprogramming, thus enabling the formation of stimulus-specific memory in innate immune sentinel cells.
2021-01-01 | GSE146068 | GEO
Project description:Macrophages initiate inflammatory responses via the transcription factor NFκB. The temporal pattern of NFκB activity determines which genes are expressed and thus, the type of response that ensues. Here, we examined how information about the stimulus is encoded in the dynamics of NFκB activity. We generated an mVenus-RelA reporter mouse line to enable high-throughput live-cell analysis of primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features—termed signaling codons—that convey stimulus information to the nucleus. In particular, oscillatory trajectories were a hallmark of responses to cytokine but not pathogen-derived stimuli. Single-cell imaging and RNA sequencing of macrophages from a mouse model of Sjögren’s syndrome revealed inappropriate responses to stimuli, suggestive of confusion of two NFκB signaling codons. Thus, the dynamics of NFκB signaling classify immune threats through six signaling codons, and signal confusion based on defective codon deployment may underlie the etiology of some inflammatory diseases.
2021-02-18 | GSE162992 | GEO
Project description:Mantle cell lymphoma (MCL) is an aggressive malignancy characterized by poor prognosis, underscoring the need for novel therapeutic strategies1. In this study, we employed large-scale pharmacological profiling of 16 pathway inhibitors across more than 100 hematological cell line models to identify novel therapeutic approaches. This screen identified a subset of MCL cell lines that were highly sensitive to the B-cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin (STN), which are currently in clinical trials2, 3. Sensitive MCL models exhibited chronic activation of the CARD11-BCL10-MALT1 (CBM) complex and dependency on downstream classical NFκB signaling. In contrast, insensitive cell lines displayed activation of the alternative NFκB pathway. Massively parallel transcriptome sequencing identified mutations in negative regulators of the alternative NFκB pathway in ibrutinib-insensitive cell lines. Notably, sequencing of 165 MCL patient samples revealed that components of the alternative NFκB pathway, particularly TRAF2 and BIRC3, are mutated in roughly 15% of MCL patients. Functional analyses of patient-derived BIRC3 mutant alleles indicated that these are loss-of-function mutants that constitutively activate alternative NFκB signaling. While being associated with insensitivity to ibrutinib, genetic lesions in the alternative pathway conferred dependence on NIK, a kinase that mediates signaling downstream of the TRAF2/3-BIRC2/3 complex. Thus, NIK represents a novel therapeutic target for MCL treatment, particularly for tumors refractory to BCR pathway inhibitors. Collectively, these findings reveal a pattern of mutually exclusive activation of the CBM-NFκB or alternative NIK-NFκB pathways in MCL and provide critical insights into patient stratification strategies for NFκB-pathway targeted agents.
| EGAS00001000622 | EGA