SSEA4 is a marker for chemotherapy resistance [miRNA]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Stefan Tomiuk
PROVIDER: E-GEOD-57704 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:By coupling PDX and cell surface marker screening technologies, we have identified distinct tumor cell sub-populations that are associated with tumor resistance to chemotherapy. In the majority of relapsed tumors, the percentage of the marker-positive cells shifted back to pretreatment levels. SSEA4 is one of the cell surface molecules tested that could distinguish enriched residual tumor cells in all the different TNBC PDX models analyzed. The expression of SSEA4 is associated with tumor resistance to chemotherapy and SSEA4+ cells show increased gene expression of genes involved in response to toxins, cellular import/export, cell migration and EMT. The dataset comprises four different sample groups including SSEA4- and SSEA4+ cell fractions isolated from mouse xenografts of human breast cancer cells. Two technical replicates were generated for each cell fraction. Microarray analysis was performed on the Agilent Whole Human Genome Oligo Microarray 8x60K (v2) platform.
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Project description:Preclinical studies of primary cancer cells are always done after tumors are removed from patients or animals at ambient atmospheric oxygen (O2, ~21%). However, O2 concentrations in organs are in the ~3-10% range, with most tumors in an hypoxic or 1-2% O2 environment in vivo. Although effects of O2 tension on tumor cell characteristics in vitro have been studied, these studies are done only after tumors are first collected and processed in ambient air. Similarly, sensitivity of primary cancer cells to anti-cancer agents is routinely examined at ambient O2. Here, using both mouse models and human cancers, we demonstrate that tumors collected, processed and propagated at physiologic (physioxia) O2 compared to ambient air display very distinct differences in key signaling networks including Lgr5/Wnt, Yap, and Nrf2/Keap1, nuclear reactive oxygen species levels, alternative splicing, and sensitivity to several targeted therapies including PIK3CAalpha-specific and EGFR inhibitors. Significance: Extra-physiologic oxygen shock/stress (EPHOSS), as noted in cells collected/processed under ambient air, has been demonstrated to have significant impact on numbers and engrafting ability of hematopoietic stem cells. We report deleterious effects of EPHOSS on cancer cell behavior and EPHOSS-mediated effects on cancer cells give misleading information on signaling pathway activation that could severely impact the relevance of these findings. Cancer cells under EPHOSS show higher proliferation rate compared to cells under physioxia and thus are sensitive to anti-proliferative agents. Thus, drugs that show effectiveness on cancer cells collected in ambient air and subjected to EPHOSS may not be effective or as relevant in vivo, results that could partially explain the limited clinical translation of laboratory findings. Evaluating cell signaling and effects of drugs on cancer cells under physiologic O2 prior to in vivo studies could substantially reduce cost and aid in drug discovery relevant to the actual physioxia/pathological status of the tumor cells in vivo.
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Project description:Background:; Yersinia outer protein (Yop) H is a secreted virulence factor of Yersinia enterocolitica which inhibits phagocytosis of Y. enterocolitica and promotes virulence of Y. enterocolitica (Ye) in mice. The aim of this study was to address whether and how YopH affects the innate immune response against Ye in mice. Results:; For this purpose mice were infected with wild type Ye (pYV+) or a YopH-deficient Ye mutant strain (DyopH). CD11b+ cells were isolated from infected spleen and subjected to gene expression analysis using microarrays. Despite attenuation of DyopH in vivo, by variation of infection doses we were able to achieve conditions that allow comparison of gene expression in pYV+ and DyopH infections at either comparable infection courses or splenic bacterial burden. Gene expression analysis provided evidence that expression levels of several immune response genes including IFN-g and IL-6 are high after pYV+ infection but low after sublethal DyopH infection. In line with these findings, infection of IFN-gR-/- and IL-6-/- mice with pYV+ or DyopH revealed that these cytokines are dispensable for control of DyopH, but not pYV+ infection. Consistently, in bacteria killing assays with BMM in vitro, stimulation of BMM with IFN-g is required for killing of pYV+ but not DyopH. Conclusion:; In conclusion, this data suggest that IFN-g counteracts YopH-mediated virulence mechanisms of Ye which in Ye wild type infection contribute to evasion of the innate immune response including killing by macrophages. Experiment Overall Design: In this study microarray analyses were performed to define differences in gene expression of cells associated with innate immune response (CD11b+ cells) after infection of mice with a sublethal and lethal infection with wildtype Yersinia enterocolitica compared to uninfected mice. In addition, we wanted to investigate whether differences in gene expression can be defined which are due to the virulence factor YopH. Moroeover, we were interested whether gene expression pattern of sublethal and lethal infected mice are different. Allover all five samples were compared. Number of replicates 1.
2008-06-11 | E-GEOD-11189 | biostudies-arrayexpress
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2012-02-01 | E-GEOD-35461 | biostudies-arrayexpress
Project description:Central questions like cardiomyocyte subtype emergence during cardiogenesis or availability of cardiomyocyte subtypes for cell replacement therapy require selective identification and purification of atrial and ventricular cardiomyocytes. However, characterization and implementation of pure cardiomyocyte subtypes is still challenging due to technical limitations. Our aim was to identify surface markers enabling the selective detection and purification of atrial and ventricular cardiomyocytes from mouse hearts. In a surface marker screen we found differential expression of CD49f in atrial and ventricular embryonic cardiomyocytes (E13.5). By flow cytometry we could correlate a high CD49f expression with MLC-2a on the single cell level; a low CD49f expression corresponded to MLC-2v. Based on the persisting differential CD49f expression we developed purification protocols for cardiomyocytes subtypes from the developing mouse heart. Flow sorting of E15.5 hearts into ErbB-2+/CD49flow and ErbB-2+/CD49fhigh cells led to a selective depletion (CD49flow) or enrichment of MLC-2a+ cells (CD49fhigh). We found a corresponding CD49f-dependent distribution of MLC-2a when pre-enriched neonatal cardiomyocytes (P2) were flow-sorted into CD49flow and CD49fhigh. Atrial and ventricular identity was confirmed by expression profiling and patch clamp analysis of sorted embryonic hearts, which unequivocally demonstrated that the sorted cells were viable and functional. For the first time, we introduce a non-genetic, antibody-based approach to specifically isolate atrial and ventricular cardiomyocytes from mouse hearts of various developmental stages. This newly gained capability of obtaining highly pure, viable cells will facilitate in-depths characterization of the individual cellular subsets and will aid translational research and therapeutic applications. The dataset comprises four different cardiomyocytes subtypes from the developing mouse heart. Embryonic (E15.5) hearts were dissociated and flow-sorted into ErbB-2+/CD49flow and ErbB-2+/CD49fhigh cardiomyocytes. Neonatal (P2) hearts were dissociated, contaminating non-myocytes were removed by MACS depletion, and the purified cardiomyocytes were flow-sorted into CD49flow and CD49fhigh cardiomyocytes. Four biological replicates were available for each sample groups. Microarray analysis was conducted on the Agilent Whole Mouse Genome Oligo Microarray 8x60K platform.
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Project description:Cancers are distributed unevenly across the body; but the importance of cell intrinsic factors such as stem cell function in determining organ cancer risk is unknown. Therefore, we used cre-recombination of conditional lineage tracing, oncogene and tumour suppressor alleles to define populations of stem and non-stem cells in mouse organs, and test their life-long susceptibility to tumorigenesis. We show that cancer risk is determined by the life-long generative capacity of mutated cells. This relationship held true in the presence of multiple genotypes and regardless of developmental stage, strongly supporting the notion that stem cells dictate organ cancer risk. Using the liver as a model system, we further show that damage-induced activation of stem cell function markedly increases cancer risk. Therefore, we propose that a combination of stem cell mutagenesis and extrinsic factors that enhance the proliferation of these cell populations, creates a âperfect stormâ that ultimately determines organ cancer risk. Long-term lineage tracing and conditional oncogenic targeting of Prom1-expressing cells in various mouse organs.
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