Xenograft models remain a cornerstone technology in the development of anti-cancer agents. The ability of immunocompromised rodents to support the growth of human tumors provides an invaluable transition between in vitro testing and clinical trials. Therefore, approaches to improve model selection are required. In this study, cDNA microarray data was generated for a collection of xenograft models at in vivo passages 1, 4 and 10 (P1, P4 and P10) along with originating cell lines (P0). These data can be mined to determine transcript expression 1) relative to other models 2) with successive in vivo passage and 3) during the in vitro (P0) to in vivo (P1) transition.
Gene expression profiling of 49 human tumor xenografts from in vitro culture through multiple in vivo passages--strategies for data mining in support of therapeutic studies.
No sample metadata fields
View SamplesDNA methylation is critical for normal development and plays important roles in genome organization and transcriptional regulation. Although DNA methyltransferases have been identified, the factors that establish and contribute to genome-wide methylation patterns remain elusive. Here, we report a high-resolution cytosine methylation map of the murine genome modulated by Lsh, a chromatin remodeling family member that has previously been shown to regulate CpG methylation at repetitive sequences. We provide evidence that Lsh also controls genome-wide cytosine methylation at nonrepeat sequences and relate those changes to alterations in H4K4me3 modification and gene expression. Deletion of Lsh alters the allocation of cytosine methylation in chromosomal regions of 50 kb to 2 Mb and, in addition, leads to changes in the methylation profile at the 5 end of genes. Furthermore, we demonstrate that loss of Lsh promotesas well as preventscytosine methylation. Our data indicate that Lsh is an epigenetic modulator that is critical for normal distribution of cytosine methylation throughout the murine genome.
Lsh, chromatin remodeling family member, modulates genome-wide cytosine methylation patterns at nonrepeat sequences.
Specimen part
View SamplesThe anti-HIV humoral immune response following acute infection is delayed and ineffective. HIV envelope protein gp120 binds to and signals through 47 on T cells. We show that gp120 also binds and signals through 47 on B cells, resulting in an abortive proliferative response. In primary B cells, gp120 signaling through 47 resulted in increased expression of TGF-1 and the B cell inhibitory receptor FcRL4. Co-culture of B cells with HIV-infected autologous CD4+ T cells also resulted in increased B cell FcRL4 expression. These findings indicate that, in addition to inducing chronic immune activation, viral proteins can contribute directly to HIV-associated B cell dysfunction, thus providing a mechanism whereby the virus subverts the early HIV-specific humoral immune response.
The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression.
Specimen part, Disease, Time
View SamplesTranscriptomic studies of human tumor xenografts are complicated by the presence of murine cellular mRNA. As such, it is useful to know the extent to which mouse mRNA cross-hybridizes to any given array platform. In this study, murine cDNA samples from diverse sources were hybridized to Affymetrix Human Genome U133 Plus 2.0 Arrays. In this regard it is possible to identify specific probes that are potential targets of cross-species interference.
Gene expression profiling of 49 human tumor xenografts from in vitro culture through multiple in vivo passages--strategies for data mining in support of therapeutic studies.
Specimen part, Cell line
View SamplesThe integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances and ER stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here we show that C/EBP:ATF4 heterodimers, but not C/EBP:ATF4 dimers, are the predominant CARE binding species in stressed cells. C/EBP and ATF4 associate with genomic CAREs in a mutually-dependent manner and co-regulate many ISR genes. By contrast, the C/EBP family members C/EBP and CHOP were largely dispensable for induction of stress genes. Cebpg/ MEFs proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpg/ mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBP-deficient newborns die from atelectasis and respiratory failure which can be mitigated by in utero exposure to the anti-oxidant, N-acetyl-cysteine. Cebpg/ mice on a mixed strain background show improved viability but, upon aging, develop significantly fewer malignant solid tumors compared to WT animals. Our findings identify C/EBP as a novel anti-oxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells.
C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4.
Specimen part
View SamplesAlveolar soft-part sarcoma (ASPS) is an extremely rare, highly vascular soft tissue sarcoma affecting predominantly adolescents and young adults. In an attempt to gain insight into the pathobiology of this enigmatic tumor, we performed the first genome-wide gene expression profiling study.
Gene expression profiling of alveolar soft-part sarcoma (ASPS).
No sample metadata fields
View SamplesTranscriptional profile of PCSC spheres in SCM-1% KO (stem-like cells) vs adherent cultures in PCSC-Celprogen medium (differentiated-like cells)
Genomic profiling of tumor initiating prostatospheres.
Specimen part, Cell line
View SamplesTumors cause the induction or repression of many genes associated with inflammation. To investigate the up and down regulation of genes associated with immune stimulation or immune tolerance RNA was isolated from dendritic cells from normal or tumor bearing prostate for microarray analysis.
FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer.
Sex, Specimen part
View SamplesTumors cause the induction or repression of many genes associated with inflammation. To investigate the up and down regulation of genes associated with immune stimulation or immune tolerance RNA was isolated from dendritic cells from normal or tumor bearing prostate for microarray analysis.
FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer.
Sex, Specimen part
View SamplesARC (NSC 188491, SMA-491), 4-amino-6-hydrazino-7-beta-d-ribofuranosyl-7H-pyrrolo-(2,3-d)-pyrimidine-5-carboxamide, is a nucleoside analog with profound in vitro anti-cancer activity. First identified in a high-throughput screen for inhibitors of p21 mRNA expression, subsequent experiments showed that ARC also repressed expression of hdm2 and survivin, leading to its classification as a global inhibitor of transcription 1. The following Hu U133 plus 2.0 arrays represent single time point (24 hour) gene expression analysis of transcripts altered by ARC treatment. Arrays for the other compounds (sangivamycin and doxorubicin) are included as comparators.
ARC (NSC 188491) has identical activity to Sangivamycin (NSC 65346) including inhibition of both P-TEFb and PKC.
No sample metadata fields
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