Dll1 dependent heterogeneity of tumor and cancer fibroblasts
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ABSTRACT:
PROVIDER: PRJNA754176 | ENA |
REPOSITORIES: ENA
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Project description:There is increasing evidence for tissue stem cells as potential source for cancers. However, the cellular and molecular mechanisms at the origin of this transformation remain elusive. Here we show that Delta-like1 (Dll1) mutation induces the oncogenic transformation of neural stem cell–derived neurospheres into oncogenic spheres capable of generating histological and molecular human glioblastoma (GBM)-like tumors upon subcutaneous and intracranial transplantations into nude mice. Serial transplantation assays suggest that Dll1 spheres tumorigenicity results from the oncogenic transformation of normal neural stem cell into GBM-producing stem cell. Compared differentiation of Dll1 vs. WT spheres shows the presence in Dll1 spheres of a subpopulation of cells which although fated to a glial lineage fail to differentiate terminally, in keeping with the astrocytic promoting function of Delta-Notch. This population of astrocyte progenitors proliferates actively and fails to down-regulate EGFR phosphorylation. These studies suggest that Dll1-induced tumorigenesis is restricted to the astrocytic lineage thereby providing a model for human GBM as well as an explanation for the duality of Notch signaling acting either as an oncogene or a tumor suppressor in stem/progenitor cells derived tumors, depending on the lineage commitment. Comparison between control (WT) and mutants (Dll1-3 and Dll1-5) cells was performed. Two biological replicates (n=3 each replicate) were used, and each replicate (n=3, total RNA pooled) was dye-swaped.
2011-09-23 | E-GEOD-32293 | biostudies-arrayexpress
Project description:Objective DLL1 is a mammalian Notch ligand with essential functions during embryonic development. We tagged endogenous DLL1 in one homologous recombination step such that AcGFP-HA tagged DLL1 could be converted by Cre-mediated site-specific recombination into StrepFlag tagged DLL1. We anticipated that this should allow us to visualise DLL1 in living cells as well as allow for sorting and enrichment of DLL1-expressing cells and efficient purification of DLL1 protein complex. Results We generated constructs to express a DLL1 variant that carried C-terminal in frame an AcGFPHA tag flanked by loxP sites followed by a StrepFlag tag out of frame. Cre-mediated recombination removed AcGFP-HA and added StrepFlag in frame to DLL1. The AcGFPHAstopStrepFlag tag was added to the Dll1 cDNA to allow for tests in cultured cells in vitro and was introduced into endogenous DLL1 in mice using ES cells modified by homologous recombination. Tagged DLL1 protein was detected by antibodies against GFP and HA or Flag, respectively, both in CHO cell and embryo lysates. In CHO cells the AcGFP protein fused to DLL1 was functional. In vivo AcGFP expression was below the level of detection by direct fluorescence. However, the StrepFlag tag allowed us to specifically purify DLL1 complexes from embryo lysates. Homozygous mice expressing AcGFPHA or StrepFlag-tagged DLL1 revealed a vertebral column phenotype reminiscent of disturbances in AP polarity during somitogenesis, a process most sensitive to reduced DLL1 function. Thus, even small C-terminal tags can impinge on sensitive developmental processes requiring DLL1 activity.
2021-11-03 | PXD024680 | Pride
Project description:There is increasing evidence for tissue stem cells as potential source for cancers. However, the cellular and molecular mechanisms at the origin of this transformation remain elusive. Here we show that Delta-like1 (Dll1) mutation induces the oncogenic transformation of neural stem cell–derived neurospheres into oncogenic spheres capable of generating histological and molecular human glioblastoma (GBM)-like tumors upon subcutaneous and intracranial transplantations into nude mice. Serial transplantation assays suggest that Dll1 spheres tumorigenicity results from the oncogenic transformation of normal neural stem cell into GBM-producing stem cell. Compared differentiation of Dll1 vs. WT spheres shows the presence in Dll1 spheres of a subpopulation of cells which although fated to a glial lineage fail to differentiate terminally, in keeping with the astrocytic promoting function of Delta-Notch. This population of astrocyte progenitors proliferates actively and fails to down-regulate EGFR phosphorylation. These studies suggest that Dll1-induced tumorigenesis is restricted to the astrocytic lineage thereby providing a model for human GBM as well as an explanation for the duality of Notch signaling acting either as an oncogene or a tumor suppressor in stem/progenitor cells derived tumors, depending on the lineage commitment.
2011-09-24 | GSE32293 | GEO
Project description:Patient derived organoids (PDOs) have been established as a 3D culture model which closely recapitulates the in vivo tumor biology. However, one limitation of this culture model is the lack of tumor microenvironment which has a significant role in tumor progression and drug response. To address this, we established and molecularly characterized a novel 3D co-culture model of colorectal cancer (CRC) based on PDOs and patient matched fibroblasts. Both normal and cancer associated fibroblasts, NFs and CAFs respectively, were able to support organoid growth without addition of niche factors to the media. Additionally, co-cultures showed closer resemblance to primary patient material than organoid mono-cultures as evaluated by histology. Finally, RNA gene expression signatures of tumor cells and fibroblasts isolated from mono- or co-cultures demonstrated that co-cultures support greater cell type heterogeneity. In this proteomics dataset we compared pairs of NFs and CAFs derived from five patients. Collectively, we present a newly established human derived organoid-fibroblast model which, closely recapitulates in vivo tumor heterogeneity and involves the tumor microenvironment.
2023-03-14 | PXD032047 | Pride
Project description:BACKGROUND: The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1(C413Y)). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized. CONCLUSIONS/SIGNIFICANCE: In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes. Four organs (liver, spleen, thymus, brain) of the Dll1 mutant mouse line analysed by cDNA microarray technology. Experiments include four biological replicates for reference (wildtype) and mutant animals. Two technical replicates for each mutant mouse were performed. As reference pooled RNA of the same organ was used. 50% of the chip hybridisations are dye sway experiments.
2009-03-01 | E-GEOD-12954 | biostudies-arrayexpress
Project description:Data generrated shows that Dll1 has several genes upregulated after targeted radiation at day 30 inlcuding EMT, ROS etc
2022-04-20 | GSE172398 | GEO