Colorectal cancer (CRC) is a heterogeneous disease classified into four consensus molecular subtype (CMSs) with distinct biological and clinical features. This study aims to understand the value of patient-derived xenografts (PDXs) in relation to these CMSs. A total of 42 primary tumors, recurrences and metastases were used to develop PDXs. Detailed genetic analyses were performed on PDXs and corresponding patient tumors to determine relationship and PDX heterogeneity. Out of 42 tumors 22 (52%) showed successfully PDX engraftment, which was biased towards metastases and CMS1 and CMS4 tumors. Importantly, gene expression analysis revealed a clinical relevant association between an engraftment gene signature and prognosis for stage II patients. Moreover, this gene signature revealed an association between Src pathway activation and positive engraftment. Src pathway activity co-aligned with CMS4 and the levels of fibronectin in tumors and was confirmed by pSrc immunohistochemistry. From this analysis we further deduced that decreased cell cycle activity is a prognostic factor for successful engraftment and related to patient prognosis. However, this is not a general phenomenon, but subtype specific as decreased cell cycle activity was highly prognostic for recurrence-free survival within CMS2 but not in CMS1 and CMS4, while it showed an inverse correlation in CMS3. These data illustrate that CRC PDX establishment is biased toward CMS1 and CMS4, which impacts translation of results derived from pre-clinical studies using PDXs. Moreover, our analysis reveals subtype-specific features, pSrc in CMS4 and low Ki67 in CMS2, which provide novel avenues for therapy and diagnosis.
Capturing colorectal cancer inter-tumor heterogeneity in patient-derived xenograft (PDX) models.
Sex, Age, Specimen part, Disease, Disease stage
View SamplesThis SuperSeries is composed of the SubSeries listed below.
MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state.
Sex, Specimen part
View SamplesWe address the molecular mechanisms through which MYC promotes loss of cell identity and acquisition of stem cell-like traits, favouring the onset of tumorigenesis, by performing gene expression profile analyses in a transition from WT IMEC, IMEC over-expressing MYC and mammospeheres formed from IMEC-MYC (named M2). We then investigated the global gene expression profile of the fraction of cells hyper-activating the WNT pathway in M2 spheres, compared to the ones with low activation
MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state.
Sex, Specimen part
View SamplesPrimary colon CSC cultures were transduced with a Wnt responsive construct (TOP-GFP) and were single cell cloned. 10% highest and lowest TOP-GFP cell fractions were FACS sorted and arrayed.
Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Genome-wide DNA methylation and gene expression analyses of monozygotic twins discordant for intelligence levels.
Specimen part
View SamplesPreviously we had shown in a mouse model of bronchial asthma that thrombomodulin (TM; CD141; BDCA3) can convert immunogenic conventional dendritic cells into tolerogenic dendritic cells while inducing its own expression on the cell surface. Thrombomodulin+ dendritic cells are tolerogenic while thrombomodulin- dendritic cells are pro-inflammatory and immunogenic. Here we hypothesized that thrombomodulin treatment of dendritic cells would modulate inflammatory gene expression. Murine bone marrow derived dendritic cells were treated with soluble thrombomodulin and expression of surface markers was determined. Treatment with thrombomodulin reduces the expression of maturation markers and increases the expression of TM on the DC surface. Thrombomodulin treated and control dendritic cells were sorted into thrombomodulin+ and thrombomodulin- dendritic cells before their mRNA was analyzed by microarray. mRNAs encoding pro-inflammatory genes and dendritic cells maturation markers were reduced while cell cycle genes were increased in thrombomodulin-treated and thrombomodulin+ dendritic cells compared to control dendritic cells and thrombomodulin- dendritic cells.
Differential gene expression in thrombomodulin (TM; CD141)(+) and TM(-) dendritic cell subsets.
Specimen part
View SamplesHuman intelligence demonstrates one of the highest heritabilities among human quantitative traits. Phenotypically discordant monozygotic twins provide a way to identify loci responsible for normal-range intelligence.
Genome-wide DNA methylation and gene expression analyses of monozygotic twins discordant for intelligence levels.
Specimen part
View SamplesProphase I of male meiosis involves dynamic chromosome segregation processes during early spermatogenesis, including synapsis, meiotic recombination, and cohesion. Genetic defects in genes participating in these processes consistently cause reproduction failure in mice. To identify candidate genes responsible for infertility in humans, we performed expression profiling of mouse spermatogenic cells undergoing meiotic prophase I.
Screening of genes involved in chromosome segregation during meiosis I: toward the identification of genes responsible for infertility in humans.
Sex, Specimen part
View SamplesProphase I of meiosis involves dynamic chromosome segregation processes including synapsis, meiotic recombination, and cohesion. Genetic defects in genes participating in these processes consistently cause reproduction failure in mice. To identify candidate genes responsible for infertility or recurrent pregnancy loss in humans, we performed expression profiling of male and female gonads of mice undergoing meiotic prophase I.
Screening of genes involved in chromosome segregation during meiosis I: in vitro gene transfer to mouse fetal oocytes.
Sex, Age, Specimen part
View SamplesThe complex of NF90 and NF45 is known to participate in transcriptional regulation, mRNA stabilization and microRNA biogenesis in vitro. However, the physiological function of the NF90-NF45 complex is still unclear. To elucidate its functions, we generated NF90-NF45 double transgenic (dbTg) mice. Robust expression of NF90 and NF45 was detected in skeletal muscle. As mentioned above, NF90-NF45 complex is involved in regulation of genes via transcription and RNA metabolism. To identify genes regulated by NF90-NF45, we performed comprehensive analyses of mRNA expression in quadriceps of wild-type (WT) and NF90-NF45 dbTg mice.
Overexpression of NF90-NF45 Represses Myogenic MicroRNA Biogenesis, Resulting in Development of Skeletal Muscle Atrophy and Centronuclear Muscle Fibers.
Sex, Age, Specimen part
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