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Homo sapiens
99 Downloadable Samples
Illumina Genome Analyzer IIx
Description
Leiomyosarcoma (LMS) is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for LMS. We demonstrate the existence of 3 molecular subtypes in a cohort of 99 cases and an independent cohort of 82 LMS. Two new FFPE tissue-compatible diagnostic immunohistochemical markers are identified: LMOD1 for subtype I LMS and ARL4C for subtype II LMS. Subtype I and subtype II LMS are associated with good and poor prognosis, respectively. The LMS subtypes show significant differences in expression levels for genes for which novel targeted therapies are being developed. Overall design: Gene expression profiling was performed by 3'' End RNA Sequencing (3SEQ), a next generation sequencing approach that does not rely on frozen tissue but can be performed on archival FFPE tissue. Samples included 99 LMS, 6 Undifferentiated Pleomorphic Sarcomas (UPS), 3 leiomyomas, 4 normal myometrium samples, and 1 case of Lymphangioleiomyomatosis (LAM). This study only includes the 99 LMS Samples. After gene expression levels were quantified by 3SEQ analysis pipeline, Consensus Clustering with bootstrap method was used to determine that the dataset contained three robust subtypes, and Silhouette analysis was performed to validate the subtype assignments. Two class SAM analysis (Significance Analysis of Microarrays) was performed to identify genes expressed differentially between each subtype of LMS with FDR of 0.05. Immunohistochemical staining was used to validate the potential diagnostic and prognostic markers from 3SEQ data on a tissue microarray.
Publication Title
Molecular subtyping of leiomyosarcoma with 3' end RNA sequencing.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Colon cancer is a major cause of cancer deaths in Western countries and is associated with diets high in red meat. Heme, the iron-porphyrin pigment of red meat, induces cytotoxicity of gut contents which injures surface cells leading to compensatory hyperproliferation of crypt cells. This hyperproliferation results in epithelial hyperplasia which increases the risk of colon cancer. In humans, a high red-meat diet increases Bacteroides spp in feces. Therefore, we simultaneously investigated the effects of dietary heme on colonic microbiota and on the host mucosa of mice. Whole genome microarrays showed that heme injured the colonic surface epithelium and induced hyperproliferation by changing the surface to crypt signaling. Using 16S rRNA phylogenetic microarrays, we investigated whether bacteria play a role in this changed signaling. Heme increased Bacteroidetes and decreased Firmicutes in colonic contents. This shift was most likely caused by a selective susceptibility of Gram-positive bacteria to heme cytotoxic fecal water, which is not observed for Gram-negative bacteria, allowing expansion of the Gram-negative community. The increased amount of Gram-negative bacteria most probably increased LPS exposure to colonocytes, however, there is no appreciable immune response detected in the heme-fed mice. There was no functional change in the sensing of the bacteria by the mucosa, as changes in inflammation pathways and Toll- like receptor signaling were not detected. This unaltered host-microbe cross-talk indicates that the changes in microbiota did not play a causal role in the observed hyperproliferation and hyperplasia.
Publication Title
Dietary heme alters microbiota and mucosa of mouse colon without functional changes in host-microbe cross-talk.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Previously, we showed that dietary heme injured the colonic surface epithelium and induced hyperproliferation by changing the surface to crypt signaling. In this study we investigated whether bacteria play a role in this changed signaling. Dietary heme increased the Bacteroidetes and decreased the Firmicutes in colonic content. This shift was caused by a selective susceptibility of Gram-positive bacteria to the heme cytotoxic fecal waters, which is not observed for Gram-negative bacteria allowing expansion of the Gram-negative community. The increased amount of Gram-negative bacteria increased LPS exposure to colonocytes, however, there is no appreciable immune response detected in the heme-fed mice. There were no signs of sensing of the bacteria by the mucosa, as changes in TLR signaling were not present. This lack of microbe-host cross talk indicated that the changes in microbiota do not play a causal role in the heme-induced hyperproliferation.
Publication Title
Dietary heme alters microbiota and mucosa of mouse colon without functional changes in host-microbe cross-talk.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Homo sapiens
- 53 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
Purpose: Multiple studies from last decades have shown that the microenvironment of carcinomas plays an important role in the initiation, progression and metastasis of cancer. Our group has previously identified novel cancer stroma gene expression signatures associated with outcome differences in breast cancer by gene expression profiling of two tumors of fibroblasts as surrogates for physiologic stromal expression patterns. The aim of this study is to find additional new types of tumor stroma gene expression patterns. Results: 53 tumors were sequenced by 3SEQ with an average of 29 million reads per sample. Both the elastofibroma (EF) and fibroma of tendon sheath (FOTS) gene signatures demonstrated robust outcome results for survival in the four breast cancer datasets. The EF signature positive breast cancers (20-33% of the cohort) demonstrated significantly better outcome for survival. In contrast, the FOTS signature positive breast cancers (11-35% of the cohort) had a worse outcome. The combined stromal signatures of EF, FOTS, and our previously identified DTF, and CSF1 signatures characterize, in part, the stromal expression profile for the tumor microenvironment for between 74%-90% of all breast cancers. Conclusions: We defined and validated two new stromal signatures in breast cancer (EF and FOTS), which are significantly associated with prognosis. Overall design: Gene expression profiling by 3SEQ was performed on 8 additional types of fibrous tumors, to identify different fibrous tumor specific gene expression signatures. We then determined the significance of the fibrous tumor gene signatures in four publically available breast cancer datasets (GSE1456, GSE4922, GSE3494, NKI Dataset).
Publication Title
Next generation sequencing-based expression profiling identifies signatures from benign stromal proliferations that define stromal components of breast cancer.
Sample Metadata Fields
Specimen part, Subject
View Samples
SRP015977- Mus musculus
- 32 Downloadable Samples
- Illumina HiSeq 2000
Description
Profile gene expression from tumors that develop in mice bearing conditional activation of EWS-ATF1, compared to control mouse tissues from the chest wall as well as tumor samples from mouse models of synovial sarcoma and osteosarcoma achieved by conditional disruption of Rb1 and p53 Overall design: 13 clear cell sarcomas (5 started with Rosa26CreER, 4 with TATCre, 2 with Prx1CreERT2, and 2 with Bmi1IRESCreERT2), 7 osteosarcomas, 6 synovial sarcomas, 6 control samples
Publication Title
Modeling clear cell sarcomagenesis in the mouse: cell of origin differentiation state impacts tumor characteristics.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 19 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st), Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Dietary haem stimulates epithelial cell turnover by downregulating feedback inhibitors of proliferation in murine colon.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The risk for colon cancer is associated with nutrition, especially high fat and low calcium diets high in red meat. Red meat contains the iron porphyrin pigment heme, which induces cytotoxicity of the colon contents and epithelial hyperproliferation. Using a mouse model, we showed that heme caused damage to the colonic surface epithelium and induced compensatory hyperproliferation. Expression levels of heme- and stress-related genes show that heme affects surface cells and not directly crypt cells. Therefore, injured surface cells should signal to crypt TA cells to induce compensatory hyperproliferation. Surface-specific downregulated inhibitors of proliferation were Wnt inhibitory factor 1, Indian Hedgehog, Bone morphogenic protein 2 and possibly Interleukin-15. Heme also upregulated Amphiregulin, Epiregulin and Cyclooxygenase-2 mRNA in the surface cells, however, their protein/metabolite levels were not increased as heme induced surface-specific translation repression by increasing 4E-BP1. Therefore, we conclude that heme induced colonic hyperproliferation and hyperplasia by repressing feedback inhibition of proliferation.
Publication Title
Dietary haem stimulates epithelial cell turnover by downregulating feedback inhibitors of proliferation in murine colon.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Mus musculus
- 3 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302), Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The risk for colon cancer is associated with nutrition, especially with diets high in red meat. Red meat contains the iron porphyrin pigment heme, which induces cytotoxicity of the colon contents and epithelial hyperproliferation. Using a mouse model, we showed that heme caused damage to the colonic surface epithelium and induced compensatory hyperproliferation. Expression levels of heme- and stress-related genes show that heme affects surface cells and not directly crypt cells. Therefore, injured surface cells should signal to crypt TA cells to induce compensatory hyperproliferation. Surface-specific downregulated inhibitors of proliferation were Wnt inhibitory factor 1, Indian Hedgehog, Bone morphogenic protein 2 and possibly Interleukin-15. Heme also upregulated Amphiregulin, Epiregulin and Cyclooxygenase-2 mRNA in the surface cells, however, their protein/metabolite levels were not increased as heme induced surface-specific translation repression by increasing 4E-BP1. Therefore, we conclude that heme induced colonic hyperproliferation and hyperplasia by repressing feedback inhibition of proliferation.
Publication Title
Dietary haem stimulates epithelial cell turnover by downregulating feedback inhibitors of proliferation in murine colon.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by luminal cytotoxicity and reactive oxygen species. This surface injury is compensated by hyperproliferation and hyperplasia of crypt cells, which was induced by a changed surface to crypt signalling as recently described. It is unknown whether the change in signaling is caused by cytotoxic stress and/or by oxidative stress, as these processes were never studied separately. Therefore, the aim of this study was to determine the possible differential effects of dietary heme on these luminal stressors and their impact on the colonic mucosa after 2, 4, 7 and 14 days of heme feeding. Mice received a purified humanized control diet or this diet supplemented with 0.2 mol heme/g. Oxidative stress was measured as Thiobarbituric Acid Reactive Substances (TBARS) in fecal water. Cytotoxicity of fecal water was quantified with a bioassay. Epithelial cell proliferation was determined by Ki67 immunohistochemistry and mucosal responses were further studied in detail by whole genome transcriptomics. Dietary heme caused instantaneous and delayed changes in the luminal contents which were reflected in the mucosa. Instantaneous, there was an increase in reactive oxygen species leading to increased levels of lipid peroxidation products. Mucosal gene expression showed an instantaneous antioxidant response and PPAR target gene activation. After day 4 cytotoxicity of the colonic contents was increased and hyperproliferation was initiated, indicating that cytotoxicity was causal for the initiation of hyperproliferation. Several oncogenes were activated and tumor protein 53 was inhibited. In conclusion, dietary heme caused an instantaneous production of reactive oxygen species in mouse colon. A lag time was observed in the formation of cytotoxicity which coincided with the initiation hyperproliferation.
Publication Title
Dietary heme induces acute oxidative stress, but delayed cytotoxicity and compensatory hyperproliferation in mouse colon.
Sample Metadata Fields
Sex, Specimen part, Time
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
The role of topographic cues in controlling commitment of induced pluripotent stem cells (iPSCs) is largely unknown. Here we demonstrate that groove-ridge nanostructures induce the elongation of iPSC colonies, guide the orientation of apical actin fibers and direct the polarity of cell division. Elongation of iPSC colonies impacts also on the intrinsic molecular patterning which seems to be orchestrated starting from the rim of the colonies. We followed the hypothesis that nanotopography directly modulates the transcriptional program of iPSC, further to guiding the overall spatial organization of the colonies. Single iPSC were seeded on flat (PI flat) and nanostructured polyimide (PI 650) and gene expression profiles were analyzed after three days. No significant differences were observed when cells were kept under culture conditions that sustained pluripotency. Then, we analyzed gene expression changes upon two weeks of multi-lineage differentiation. Many genes revealed significant expression changes in the course of differentiation and this was more pronounced on PI flat as compared to PI 650. Comparison of iPSC that were either differentiated on flat or nanostructured biomaterials revealed differential expression of several genes. Noteworthy, among significantly regulated genes, the biggest fold change on PI 650 versus PI flat after differentiation was observed in ANKRD1, which is one of the best readouts of YAP/TAZ activity. Our study suggests that nanotopography impacts on orientation and organization of iPSC colonies and highlight a possible interaction between mechanosensors and mechanotransducers.
Publication Title
Surface Topography Guides Morphology and Spatial Patterning of Induced Pluripotent Stem Cell Colonies.
Sample Metadata Fields
Specimen part, Subject
View Samples