Targetable programs of adult cancer are ontogenically rooted within early cell fate trajectories of human pluripotent state [array]
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PROVIDER: PRJNA549762 | ENA |
REPOSITORIES: ENA
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Project description:Targetable programs of adult cancer are ontogenically rooted within early cell fate trajectories of human pluripotent state
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Project description:Targetable programs of adult cancer are ontogenically rooted within early specified cell fate trajectories of human pluripotency
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Project description:Recognized molecular similarities between pluripotency and cancer have recently been underscored with multi-omics campaigns revealing stemness networks that are shared between human pluripotent stem cells (hPSCs) and tumors, where tumors types cluster based on tissue origins. Informed by these in silico studies, we now demonstrate hPSCs serve as a source of networks that define properties of adult tissue oncogenesis. Single cell deconstruction of hPSCs allowed germ layer primed subsets to be identified that corresponded to lineage specified adult cancers. Chemical probes that induced germ layer differentiation of hPSCs also suppressed adult cancers, but were restricted to tumors of shared origin with germ layer specification. Metallothioneines induced mesoderm differentiation of hPSC with exclusive ability to overcome differentiation block of human leukemia. Our study provides causal evidence for a relationship between pluripotent state and human cancer that defines oncogenic reprogramming and thereby identify covert targets for cancer therapy.
2023-05-17 | GSE133041 | GEO
Project description:Molecular similarities between pluripotency and cancer have recently been underscored by multi-omics campaigns revealing stemness networks that are shared between human pluripotent stem cells (hPSCs) and tumors, as well as tumor types that cluster based on tissue origins. Informed by these in silico studies, we now demonstrate that hPSCs serve as a cellular source to define properties of adult tissue oncogenesis. Single cell deconstruction of hPSCs allowed germ layer primed subsets to be identified that corresponded to lineage specified adult cancers. Functionally, chemical probes that induce hPSC germ layer specification suppressed adult cancer growth, but were restricted to tumors that correspond with shared germ layer origins. For example, metallothioneins induced mesoderm differentiation of hPSC and showed exclusive ability to overcome differentiation block of human leukemia. Our study provides causal evidence for oncogenic reprogramming to define a relationship between pluripotent state and human cancers that can identify covert targets for cancer therapies.
2023-05-17 | GSE133669 | GEO
Project description:Recognized molecular similarities between pluripotency and cancer have recently been underscored with multi-omics campaigns revealing stemness networks that are shared between human pluripotent stem cells (hPSCs) and tumors, where tumors types cluster based on tissue origins. Informed by these in silico studies, we now demonstrate hPSCs serve as a source of networks that define properties of adult tissue oncogenesis. Single cell deconstruction of hPSCs allowed germ layer primed subsets to be identified that corresponded to lineage specified adult cancers. Chemical probes that induced germ layer differentiation of hPSCs also suppressed adult cancers, but were restricted to tumors of shared origin with germ layer specification. Metallothioneines induced mesoderm differentiation of hPSC with exclusive ability to overcome differentiation block of human leukemia. Our study provides causal evidence for a relationship between pluripotent state and human cancer that defines oncogenic reprogramming and thereby identify covert targets for cancer therapy
2023-06-30 | GSE132567 | GEO
Project description:Cancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast cancer is not a disease of a singular origin. Multiple epithelial populations serve as the culprit cell-of-origin for specific breast cancer subtypes, yet our knowledge of the metabolic network of normal mammary epithelial cells is limited. Using a multi-OMIC approach, here we identify the diverse metabolic programs operating in normal mammary populations. The proteomes of basal, luminal progenitor, and mature luminal cell populations revealed enrichment of glycolysis in basal cells and of oxidative phosphorylation in luminal progenitors. Single-cell transcriptomes corroborated lineage-specific metabolic identities and additional intra-lineage heterogeneity. Mitochondrial form-and-function differed across lineages, with clonogenicity correlating to mitochondrial activity. Targeting oxidative phosphorylation and glycolysis with inhibitors exposed lineage-rooted metabolic vulnerabilities of mammary progenitors. Bioinformatics indicated breast cancer subtypes retain metabolic features of their putative cell-of-origin. Thus, lineage-rooted metabolic identities of normal mammary cells may underlie breast cancer metabolic heterogeneity and targeting these vulnerabilities could advance breast cancer therapy.
2021-04-28 | GSE168660 | GEO
Project description:Mammary epithelial cells have lineage-rooted metabolic identities
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Project description:This GEO series contains human scRNA-seq data of Neuroblastoma patients, used in two manuscripts. n=7 paired samples, primary tumour vs. bone marrow metastases n=2 non-paired samples, bone marrow metastases Titles: Article 1 PUBLISHED: Neuroblastoma plasticity during metastatic progression stems from the dynamics of an early sympathetic transcriptomic trajectory See Citation and PubMed ID below. Article 2 UNDER REVIEW: Single-cell analyses of paired primary neuroblastoma tumor and bone marrow metastases reveals intra-patient heterogeneity and therapy-resistant subpopulations Abstract of article 1: Despite their indisputable importance in neuroblastoma (NB) pathology, knowledge of the bases of NB plasticity and heterogeneity remains incomplete. They may be rooted in developmental trajectories of their lineage of origin, the sympatho-adrenal neural crest. We found that implanting human NB cells in the neural crest of the avian embryo allows recapitulating the metastatic sequence until bone marrow involvement. Using deep single cell RNA sequencing, we characterized transcriptome states of NB cells and their dynamics over time and space, and compared them to those of fetal sympatho-adrenal tissues and patient tumors and bone marrow samples. Here we report remarkable transcriptomic proximities restricted to an early sympathetic neuroblast branch that co-exist with phenotypical adaptations over disease progression and recapitulate intratumor and interpatient heterogeneity. Combining avian and patient datasets, we identified a list of genes upregulated upon bone marrow involvement and associated with growth dependency, validating the relevance of our multimodal approach. Despite being key pathological features, Neuroblastoma (NB) plasticity and Heterogeneity remain largely misunderstood. They may be rooted in complex developmental trajectories of their embryonic lineage of origin, the sympatho-adrenal neural crest. We found that implanting human NB cells in the neural crest of the avian embryo allows recapitulating the metastatic sequence until bone marrow involvement. Using deep single cell RNA sequencing, we characterized transcriptional states of NB cells and their dynamics over time and space, and compared them to those of fetal sympatho-adrenal tissues and patient tumors, including matched primary tumor and bone marrow samples. We found remarkable transcriptomic proximities restricted to an early sympathetic neuroblast branch that co-exist with phenotypical adaptations over disease progression and recapitulate intratumor and interpatient heterogeneity. Combining avian model and patient datasets, we identified a list of candidate genes upon bone marrow involvement associated with NB growth dependency, validating the relevance of our multimodal approach.
2024-09-13 | GSE245175 | GEO
Project description:Dynamic changes to the epigenome mediate key neurobiological and cognitive processes in the central nervous system, and also play a role in transcriptional regulation during brain development. Although the importance of DNA methylation in brain development is highlighted by the neurodevelopmental deficits associated with mutations in genes including methyl-CpG binding protein 2 (MECP2), our knowledge about the specific methylomic trajectories associated with human neurodevelopment is extremely limited. Here we report an analysis of genome-wide patterns of DNA methylation in 179 human fetal cortex samples. Bisulphite converted DNA from 179 human brain samples was hybridized to the Illumina 450K Human Methylation Beadchip.
2014-12-19 | E-GEOD-58885 | biostudies-arrayexpress
Project description:Biologists rely on morphology, function, and specific markers to define the differentiation status of cells. Transcript profiling has expanded the repertoire of these markers by providing the snapshot of cellular status that reflects the activity of all genes. However, such data have been used only to assess relative similarities and differences of these cells. Here we show that principal component analysis (PCA) of global gene expression profiles map cells in multidimensional transcript profile space and the positions of differentiating cells progress in a stepwise manner along trajectories starting from undifferentiated embryonic stem (ES) cells located in the apex. We present three cell lineage trajectories, which represent the differentiation of ES cells into the first three lineages in mammalian development: primitive endoderm, trophoblast, and primitive ectoderm/neural ectoderm. The positions of the cells along these trajectories seem to reflect the developmental potency of cells and can be used as a scale for the potential of cells. Indeed, we show that embryonic germ (EG) cells and induced pluripotent (iPS) cells are mapped near the origin of the trajectories, whereas mouse embryo fibroblast (MEF) and fibroblast cell lines are mapped near the far end of the trajectories. We propose that this method can be used as the non-operational semi-quantitative definition of cell differentiation status and developmental potency. Furthermore, the global expression profiles of cell lineages provide a framework for the future study of in vitro and in vivo cell differentiation. Keywords: cell type comparison design,reference design,replicate design,time series design Most of the cells and RNA samples used in this study were described in detail previously (See paper's citation associated with this dataset). To maximize the uniformity of the microarray data, all the samples, including ones analyzed by DNA microarray previously, were hybridized to the same platform (the NIA Mouse 44K Microarray manufactured by Agilent Technologies: AMADID #015087). The intensity of each gene feature per array was extracted from scanned microarray images using Feature Extraction Software V9.5.
2008-12-27 | E-GEOD-11523 | biostudies-arrayexpress