Glioblastoma cell malignancy and drug sensitivity are affected by the cell of origin
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PROVIDER: PRJNA356891 | ENA |
REPOSITORIES: ENA
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Project description:The cell of origin in glioblastoma is not formally proven but generally accepted to be a neural stem cell or glial precursor cell. In addition, there is also limited knowledge about the functional consequences of the cell of origin for glioblastoma development and response to therapy. We have investigated the role of cell of origin in glioblastoma by inducing glioblastomas of defined cell of origin using PDGFB in the brains of adult mice. Gene expression was analysed from cultured mouse glioblastoma cells and a mouse cell origin gene signature was extracted that we used in a cluster analysis on gene expression data from patient-derived glioblastoma cell lines.
2017-01-23 | GSE91392 | GEO
Project description:The cell of origin in glioblastoma is not formally proven but generally accepted to be a neural stem cell or glial precursor cell. In addition, there is also limited knowledge about the functional consequences of the cell of origin for glioblastoma development and response to therapy. We have investigated the role of cell of origin in glioblastoma by inducing glioblastomas of defined cell of origin using PDGFB in the brains of adult mice. Gene expression was analysed from cultured mouse glioblastoma cells and a mouse cell origin gene signature was extracted that we used in a cluster analysis on gene expression data from patient-derived glioblastoma cell lines.
2017-01-23 | GSE91391 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-01-23 | GSE91393 | GEO
Project description:Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition
| PRJNA641376 | ENA
Project description:Previous studies have established that the cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity. However, the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to cytotoxic chemotherapy and express high levels of the transcription factor Evi1 compared to leukemias derived from myeloid progenitors. Here, we compared drug sensitivity and expression profiles of murine and human leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for Evi1 in modulating p53 protein stability and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 inhibitors in addition to classical genotoxic stresses. p53 loss-of-function in Evi1low progenitor-derived leukemias induces resistance to LSD1 inhibition. By contrast, Evi1high leukemias are sensitized to LSD1 inhibition by the BH3 mimetic venetoclax, resulting in enhanced apoptosis and greater reductions in disease burden. Our findings demonstrate a cell-of-origin determined novel role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in high-risk, chemoresistant EVI1high AML.
2020-07-29 | GSE153025 | GEO
Project description:Mouse expression data from Glioblastoma cell malignancy and drug sensitivity are affected by the cell of origin.
| PRJNA356893 | ENA
Project description:Human expression data from Glioblastoma cell malignancy and drug sensitivity are affected by the cell of origin.
| PRJNA356892 | ENA
Project description:Cancer results from molecular mutations occurring in specific cell types, thus determining the cell-of-origin is critical for effective cancer treatment. Inferring such information from terminal tumors can be misleading because malignant tumor cells tend to acquire aberrant properties. Animal models are widely used because one can initiate mutations in specific cell types. However, cell-of-mutation that harbors initial molecular changes may not directly transform, rather merely passes along mutations to its progeny cell lineage, which then serves as cell-of-origin and finally transforms into malignancy. Such a problem is exemplified in the glioma field: glioma can be induced either by mutating tumor suppressor genes in neural stem cells (NSCs) or by over-expressing oncogenes in restricted progenitor cells such as oligodendrocyte precursor cells (OPCs). However, for the NSC glioma model, it remains unknown whether NSCs directly transform or simply pass along mutations to OPC lineage for malignancy. Here we use a genetic system termed Mosaic Analysis with Double Markers (MADM) to study the earliest stage of gliomagenesis from mutated NSCs. At an in vivo single-cell resolution, we unbiasedly analyzed tumorigenic potential of NSCs and all cell lineages derived from them. At pathologically undetectable pre-transforming phases, we found no significant aberrant growth of mutant NSCs and their derivatives except for the OPC lineage. We then tracked the tumor progression from earliest stage and confirmed the expansion of OPCs lead to gliomagenesis. Consistently, transcriptome profiling reveals that terminal-stage tumor cells display salient OPC features and resemble human proneural subtype of glioblastoma multiform (GBM). Most importantly, introducing the same mutations directly into OPCs was sufficient for malignant transformation and these tumor cells are indistinguishable in their gene expression profiles from those in which the first mutations were introduced into NSCs. Our findings strongly implicate OPCs as the transforming cell type for glioma even when initial mutations could occur in NSCs, and highlight the importance of analyzing early phases of tumorigenesis to distinguish cell-of-origin from cell-of-mutation. 44K Mouse Development Oligo Microarrays from Agilent Technologies were used for microarray analysis. For each experiment, total RNA was fluorescently labeled and hybridized directly against a common reference sample generated from the RNA pool of four WT P17 mouse brain neocortex.
2011-07-01 | E-GEOD-26676 | biostudies-arrayexpress
Project description:We examined the relationship between miRNA expression and the sensitivity of CCA cells to Gem. Two intrahepatic CCA cell lines, HuH28 and HuCCT1 were used. HuCCT1 cells were more sensitive to Gem than were HuH28 cells. The miRNA expression profiles of HuH28 and HuCCT1 were determined by microarray analysis. Eighteen miRNAs were differentially expressed whose ratios over ± 2log2 between HuH28 and HuCCT1. Among these 18 miRNAs, ectopic overexpression of each of three downregulated miRNAs in HuH28 (miR-29b, miR-205, miR-221) restored Gem sensitivity to HuH28. Suppression of one upregulated miRNA in HuH28, miR-125a-5p, inhibited HuH28 cell proliferation independently to Gem treatment.
2013-06-02 | GSE47396 | GEO
Project description:Aging is associated with significant changes in the hematopoietic system, including increased inflammation, impaired hematopoietic stem cell (HSC) function, and increased incidence of myeloid malignancy. Inflammation of aging (“inflammaging”) has been proposed as a driver of age-related changes in HSC function and myeloid malignancy, but mechanisms linking these phenomena remain poorly defined. Here, we identify loss of miR-146a as driving aging-associated inflammation in AML patients. miR-146a expression declined in old wild-type mice, and loss of miR-146a promoted premature HSC aging and inflammation in young miR-146a-null mice, preceding development of aging-associated myeloid malignancy. Using single-cell assays of HSC quiescence, stemness, differentiation potential, and epigenetic state to probe HSC function and population structure, we found that loss of miR-146a depleted a subpopulation of primitive, quiescent HSCs. DNA methylation and transcriptome profiling implicated NF-κB, IL6, and TNF as potential drivers of HSC dysfunction, activating an inflammatory signaling relay promoting IL6 and TNF secretion from mature miR-146a-/- myeloid and lymphoid cells. Reducing inflammation by targeting Il6 or Tnf was sufficient to restore single-cell measures of miR-146a-/- HSC function and subpopulation structure, and reduced the incidence of hematological malignancy in miR 146a-/- mice. miR-146a-/- HSCs exhibited enhanced sensitivity to IL6 stimulation, indicating that loss of miR-146a affects HSC function via both cell-extrinsic inflammatory signals and increased cell-intrinsic sensitivity to inflammation. Thus, loss of miR 146a regulates cell-extrinsic and -intrinsic mechanisms linking HSC inflammaging to the development of myeloid malignancy.
2020-05-14 | GSE148988 | GEO