ASC deficiency suppresses proliferation and prevents medulloblastoma incidence
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Mohanish Deshmukh
PROVIDER: E-GEOD-48682 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC's role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knockout mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both wild-type and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC-deficient SmoA1 cerebella exhibited disrupted expression of genes in the transforming growth factor-β pathway and increased level of nuclear Smad3. Taken together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for antitumor therapy.
2014-05-23 | GSE48682 | GEO
Project description:Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common malignant tumor of the central nervous system. About 20-30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogene Smoothened is a key transducer of the Shh pathway. Activating mutations in Smoothened that lead to constitutive activity of the Shh pathway have been identified in human medulloblastoma. To understand the molecular and cellular effects of Smoothened variants in normal development and medulloblastoma genesis, we generated the SmoA2 transgenic mouse model which expresses the transgene exclusively in granule neuron precursors. In this study, we demonstrate how two point mutations in a single molecule can produce starkly different phenotypes as seen in comparison to our previous model, ND2:SmoA1. The SmoA2 mice have severe aberrations in cerebellar development whereas the SmoA1 mice are largely normal during development. Medulloblastomas in the SmoA2 mice develop in the dysplastic cerebellar milieu. Intriguingly, despite disruptions in the stereotypic organization of the cerebellum, the SmoA2 mice do not exhibit any overt abnormalities in motor coordination. The differences in the global transcriptional profiles downstream of SmoA1 and SmoA2 further demonstrate the distinctiveness of the two oncogenic Smoothened mutations. The SmoA2 model serves as a unique spatiotemporal tool to investigate the functional significance of the reiterative cerebellar circuitry as well as to further understand Shh pathway mechanics in cerebellar development and oncogenesis. We previously generated a SmoA1 transgenic mouse medulloblastoma model, which expresses the SmoA1 transgene driven by the GNP-specific fragment of the promoter of ND2 transcription factor leading to constitutively active Shh signaling exclusively in the cerebellum. In this study, we characterize the ND2:SmoA2 transgenic mouse model with a similarly designed transgene expressing the SmoA2 mutation. To assess transcriptional changes downstream of SmoA1 and SmoA2, we evaluated global gene expression profiles of P5 SmoA1, SmoA2 and Wt age-matched cerebella. We chose this specific developmental stage because (1) the phenotypes of SmoA1 and SmoA2 are robust and distinct at P5; (2) at P5 GNPs undergo proliferation, migration and differentiation and therefore expression profiling could capture key differences in multiple processes.
2012-11-02 | E-GEOD-34593 | biostudies-arrayexpress
Project description:Triple-negative (TN) and Basal-like (BL) breast cancer definitions have been used interchangeably to identify breast cancers that lack expression of the hormonal receptors (HR) and overexpression and/or amplification of HER2. However, both classifications when compared to each other, show substantial discordance rates. Here, we molecularly characterize TN tumors, and Basal-like tumors, and compare and contrast the results in terms of common patterns and distinct patterns for each. In total, when testing 412 TN and 473 Basal-like tumors, 21.4% and 31.5% were identified as non-Basal-like and non-TN, respectively. TN tumors identified as Luminal or HER2-enriched showed undistinguishable overall gene expression profiles when compared versus Luminal or HER2-enriched tumors that were not TN. Similar findings were observed within Basal-like tumors regardless of the TN status. Interestingly, most TN tumors identified as HER2-enriched showed low HER2 expression and lack of HER2 amplification despite the similar overall gene expression profiles to HER2-E tumors that were not TN. Lastly, additional genomic classifications are examined within TN and Basal-like cancers, most of which are largely concordant with tumor intrinsic subtype. These results suggest that future clinical trials focused on TN disease should consider stratifying patients based on Basal-like versus non-Basal-like gene expression profiles as this appears to be the main biological difference seen within TN breast cancer patients. reference x sample
2014-07-29 | E-GEOD-41119 | biostudies-arrayexpress
Project description:End-stage breast cancers are clonally heterogeneous and harbor many poorly-understood treatment resistance mechanisms. We therefore established multiple Patient-Derived-Xenograft (PDX) models to study genomic events driving advanced disease. Comparative whole-genome sequencing of paired primary tumors and their PDX models demonstrated that PDX retain the vast majority of the structural variations and copy number aberrations seen within the originating tumor, and with high fidelity. Variant allele fractions (VAF) were preserved, even for rare mutations. Clonal representation is therefore a transplantable phenotype, indicating that genomic heterogeneity can be regulated in a tumor-autonomous mechanism, indifferent to host immune status. Mutations and gene rearrangements were documented in the ESR1 gene in three of five sequenced luminal PDX/progenitor tumor pairs (amplification, point mutation and translocation), and were associated with clinical endocrine response phenotypes, differential PDX estradiol responsiveness and all induced estradiol-independent growth in standard cell lines. PDX models are therefore a significant new tool for fundamental studies on the molecular basis for resistance to endocrine treatment in advanced breast cancer. reference x sample
2013-12-22 | E-GEOD-46604 | biostudies-arrayexpress
Project description:Interactions of cancer cells with the vasculature are essential for tumor growth and likely promote metastatic progression. Endothelial cell content and lympho-vascular invasion are generally associated with tumor aggressiveness, however, these features are generally not employed in the clinic. We aimed to determine if endothelial cell gene expression signatures could be utilized to better characterize breast tumor biology, and to establish if vascular cell-derived signatures could provide information to predict tumors likely to metastasize. Here we report on the identification of a gene signature for vascular endothelial cells, and a second for cancer-activated vasculature. Both signatures independently identify subsets of aggressive breast cancers. Interestingly, the vascular content signature and a previously identified hypoxia signature both provide prognostic information beyond currently utilized clinical parameters and intrinsic subtype classifications. In these studies, we also examined the relationship that the breast cancer subtypes have with vascular gene expression profiles, and found that claudin-low tumors and cell lines express vascular gene expression profiles and displayed endothelial-like tube formation when grown in three-dimensions. These findings are directly applicable to clinical care and therapeutic treatment design as they identify highly aggressive subsets of tumors with genetic and morphologic vascular properties. reference x sample
2014-01-01 | E-GEOD-37145 | biostudies-arrayexpress
Project description:Background: Age is the strongest breast cancer risk factor, with overall breast cancer risk increasing steadily beginning at approximately 30 years of age. However, while breast cancer risk is lower among younger women, young women’s breast cancer may be more aggressive. Though several genomic and epidemiologic studies have shown higher prevalence of aggressive, estrogen-receptor negative breast cancer in younger women, the age-related gene expression that predisposes to these tumors is poorly understood. Characterizing age-related patterns of gene expression in normal breast tissues may provide insights on etiology of distinct breast cancer subtypes that arise from these tissues. Methods: To identify age-related changes in normal breast tissue, 96 tissue specimens from reduction mammoplasty patients aged 14 to 70 were assayed by gene expression microarray. Results: Significant associations between gene expression levels and age were identified for 802 probes (481 increased, 321 decreased with increasing age). Enriched functions included ‘aging of cells’, ‘shape change’, and ‘chemotaxis’, and enriched pathways included Wnt/beta-catenin signaling, Ephrin Receptor Signaling, and JAK/Stat Signaling. Applying the age-associated genes to publicly available tumor datasets, the age-associated pathways defined two groups of tumors with distinct survival. Conclusion: The hazard rates of young-like tumors mirrored that of high grade tumors in the Surveillance, Epidemiology and End Results Program, providing a biological link between normal aging and age-related tumor aggressiveness. Impact: These data show that studies of normal tissue gene expression can yield important insights about the pathways and biological pressures that are relevant during tumor etiology and progression. reference x sample
2013-08-31 | E-GEOD-43973 | biostudies-arrayexpress
Project description:Introduction: In breast cancers, the basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. There is evidence that this genomic instability extends to smaller scale genomic aberrations as well, as shown by a previously described micro-event in the PTEN gene in the Basal-like SUM149 breast cancer cell line. Methods: We sought to identify if small regions of genomic change exist by using a high density, gene centric Comparative Genomic Hybridizations (CGH) array on both cell lines and primary tumors. A custom Agilent tiling array for CGH (244,000 probes, 200bp tiling resolution) was created to identify small regions of genomic change and was focused on previously identified basal-like-specific, and general cancer genes. Tumor genomic DNA from 94 patients and 2 breast cancer cell lines was labeled and hybridized to these arrays. Aberrations were called using SWITCHdna and the smallest 25% of SWITCHdna-defined genomic segments being called micro-aberrations (<64 contiguous probes, ~ <15kb). Results: Our data showed that primary tumor breast cancer genomes frequently contained areas of small-scale copy number gains and losses, termed micro-aberrations, which are undetectable using lower-density genome-wide platforms. The basal-like subtype exhibited the highest incidence of these events. These micro-aberrations sometimes altered expression of the involved gene as suggested by data from microarray and mRNA-seq studies. We confirmed the presence of the PTEN micro-amplification in SUM149 and by mRNA-seq showed that this resulted in loss of expression of all exons downstream of this event. Micro-aberrations disproportionately affected the 5’ regions of the affected genes, including the promoter region, and a high frequency of micro-aberrations was associated with poor survival outcomes. Conclusion: Using a high probe density, gene-centric aCGH microarray, we present evidence of small-scale genomic aberrations that contribute to gene inactivation, and thus, genomic instability and tumor formation through a mechanism not detected using conventional copy number analyses. reference x sample
2013-04-22 | E-GEOD-36889 | biostudies-arrayexpress
Project description:Five molecular subtypes (Luminal A/B, HER2-enriched, Basal-like, and Claudin-low) with clinical implications have been identified. In this report, we evaluated molecular and phenotypic relationships of a large in vitro panel of human breast cancer cell lines (BCCLs), human mammary fibroblasts (HMFs) and human mammary epithelial cells (HMECs) with (1) breast tumors, (2) normal breast cell-enriched subpopulations and (3) human embryonic stem cells (hESCs) and bone marrow-derived mesenchymal stem cells (hMSC). First, by integrating genomic data of 337 breast samples with 93 cell lines we were able to identify all the intrinsic tumor subtypes in vitro, except for the Luminal A. Secondly, we observed that cell lines recapitulate the differentiation hierarchy observed in the mammary gland, with Claudin-low BCCLs and HMFs cells showing a stromal phenotype, HMECs showing a mammary stem cell/bipotent progenitor phenotype, Basal-like cells showing a luminal progenitor phenotype, and Luminal B cells showing a luminal phenotype. Thirdly, we identified Basal-like and highly migratory Claudin-low subpopulations of cells within a subset of triple-negative BCCLs (SUM149PT, HCC1143 and HCC38). Interestingly, both subpopulations within SUM149PT where found to have Tumor Initiating Cell (TIC) features, but the Basal-like subpopulation grew faster than the Claudin-low subpopulation. Finally, Claudin-low BCCLs were found to resemble the phenotype of hMSCs, whereas hESCs cells were found to have an epithelial phenotype without basal and luminal differentiation. The results presented here should help improve our understanding of the cell line model system through the appropriate pairing of cell lines with relevant in vivo tumor and normal cell counterparts. reference x sample
2013-10-29 | E-GEOD-50470 | biostudies-arrayexpress
Project description:The ability to predict metastatic potential is of clinical and biological importance. Numerous metastasis/relapse predictors exist for breast cancer patients; however, what is less well established is whether predicting metastasis to specific organs sites is feasible. In this study we sought to determine: 1) the degree to which gene signatures vary across tumors and their metastases, 2) if genomic intrinsic subtypes associate with particular organs of relapse, and 3) if other genomic signatures can predict spread to specific organs. Using a gene expression microarray data set of >1000 breast tumors and metastases, we observed that >90% of 298 gene signatures were similarly expressed between matched pairs of breast tumors and metastases; those most altered were reflective of cell types including fibroblasts and immune cells. Significant associations were identified between tumor subtypes and organ of first relapse. Among these, HER2-enriched tumors were significantly associated with liver, and Basal-like and Claudin-low tumors with brain and lung. Correspondingly, previously published brain and lung metastasis signatures, along with embryonic stem cell and tumor initiating cell signatures, were also associated with Basal-like and Claudin-low subtypes. These signatures strongly correlated with low Differentiation Scores (DS) and, to a lesser extent, high proliferation. Interestingly, within Basal-like and Claudin-low tumors, low DS further predicted for brain and lung metastases. In total, intrinsic subtype and DS provide clinically useful information that identifies the distant organ sites that should be most closely monitored for signs of disease recurrence. 414 samples profiled on Agilent microarrays.
2011-06-20 | E-GEOD-26338 | biostudies-arrayexpress
Project description:Chemotherapy resistance frequently drives tumor progression. However, the underlying molecular mechanisms are poorly characterized. Epithelial-to-mesenchymal transition (EMT) has been shown to correlate with therapy resistance, but the functional link and signaling pathways remain to be elucidated. We report here that miR-30c, a human breast tumor prognostic marker, plays a pivotal role in chemo-resistance by a direct targeting of the actin-transporter TWF1, which promotes EMT. An IL-6 family member, IL-11 was identified as a secondary target of TWF1 in the miR-30c signaling pathway. Expression of miR-30c inversely correlated with IL-11 expression in clinical tumors and IL-11 correlated with relapse-free survival in breast cancer patients. Identification of a novel miRNA-mediated pathway that regulates chemo-resistance in breast cancer will facilitate the development of new management strategies. reference x sample
2013-01-18 | E-GEOD-22049 | biostudies-arrayexpress