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Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors

ABSTRACT: Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant brain tumor in infants and is characterized by loss of nuclear SMARCB1 protein expression. Recent studies show that AT/RTs comprise three molecular subgroups with epigenetic differences, including distinct expression patterns of genes involved in ciliogenesis, but little is known on the functional role of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. Finally, we demonstrated significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis, confirming a survival benefit across different species with SMARCB1 deficiency. Altogether, our findings indicate that targeting primary ciliogenesis or its downstream signaling may constitute a novel therapeutic approach for AT/RT.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179668 | GEO | 2022/09/19

REPOSITORIES: GEO

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Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors

Project description:Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant brain tumor in infants and is characterized by loss of nuclear SMARCB1 protein expression. Recent studies show that AT/RTs comprise three molecular subgroups with epigenetic differences, including distinct expression patterns of genes involved in ciliogenesis, but little is known on the functional role of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. Finally, we demonstrated significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis, confirming a survival benefit across different species with SMARCB1 deficiency. Altogether, our findings indicate that targeting primary ciliogenesis or its downstream signaling may constitute a novel therapeutic approach for AT/RT.

2022-10-14 | PXD027211 | Pride

The genomic and epigenomic landscape of atypical teratoid rhabdoid tumors

Project description:Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large series of human ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.

2016-03-02 | GSE70460 | GEO

Study of SPEN knockdown in MCF10A cells

Project description:In this experiment, we knocked down the expression of Split Ends (SPEN), a gene that we found was involved in the regulation of primary cilia formation, in MCF10A cells, to evaluate its effects on transcription. Split Ends (SPEN) is a transcriptional coregulator that have formerly identified as a tumour suppressor gene in ER-positive breast cancers. We expect the knockdown of SPEN in MCF10A cells to be accompanied with the down-regulation of genes involved in ciliogenesis as we observed that SPEN knockdown decreases primary cilia formation in those cells. We chose MCF10A cells because they harbour lots of primary cilia and therefore represent a good model to study the effect of SPEN on primary cilia formation.

2017-08-15 | E-MTAB-4974 | biostudies-arrayexpress

Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors.

Project description:Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS-tumors of infancy and early childhood. Hallmark is the surprisingly simple genomics with a truncating mutation in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T-cells. However, it is unclear, what T-cells might recognize on AT/RT cells. Here, we report a comprehensive analysis of naturally presented HLA-class-I and class-II ligands on n=23 AT/RTs. MS-based analysis of the HLA-ligandome revealed 55 class-I and 139 class-II peptides from tumor-associated proteins.

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miR-129-3p control cilia assembly by regulating CP110 and actin dynamics [miR-129-3p overexpression]

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2012-05-31 | E-GEOD-34846 | biostudies-arrayexpress

Transcriptional profiling of C. elegans DAF-19 uncovers a ciliary base-associated protein and a CDK/CCRK/LF2p-related kinase required for intraflagellar transport.

Project description:Cilia are ubiquitous cell surface projections that modulate various sensory- and motility based processes and are implicated in a growing number of multi-organ genetic disorders termed ciliopathies. As new components required for cilium biogenesis and function remain unidentified, we sought to further define and validate the transcriptional targets of the ciliogenic C. elegans RFX transcription factor DAF-19. To this end, transcriptional profiling of daf-19 mutants (which do not form cilia) and wild-type animals was performed using selectively staged embryos where ciliogenesis occurs in most ciliated sensory neurons (CSNs). Statistical comparisons between the two populations revealed 881 differentially regulated genes with 1.5-fold change or greater. A subset of these was confirmed by quantitative RT-PCR. Transgenic worms expressing transcriptional-GFP fusions revealed CSN-specific expression patterns for 9 of 12 candidate genes. We show that two uncharacterized candidate genes, which we term dyf-17 and dyf-18 because their corresponding mutants display dye-filling (Dyf) defects, are important for ciliogenesis. DYF-17 localizes at the base of cilia and interestingly, is specifically required for building the distal segment of sensory cilia. DYF-18 is an evolutionarily conserved CDK-7/CCRK-related serine-threonine kinase that is necessary for the proper function of intraflagellar transport (IFT), a process critical for cilium biogenesis. Together, our comparative microarray study identifies targets of the evolutionarily conserved RFX transcription factor, DAF-19, providing a rich dataset from which to uncover—in addition to DYF-17 and DYF-18—cellular components important for cilium formation and function. 4 daf-19,daf12; 4 daf-12; 4 WT

2011-07-25 | E-GEOD-25633 | biostudies-arrayexpress

EZH2-mediated primary cilium deconstruction drives metastatic melanoma formation

Project description:Human melanomas frequently harbor amplifications of EZH2. However, the oncogenic contribution of this methyltransferase to melanoma formation has remained elusive. Taking advantage of murine melanoma models, we now show that EZH2 drives tumorigenesis from benign BrafV600E or NrasQ61K-expressing melanocytes. EZH2 oncogenicity results from silencing of genes relevant for the integrity of the primary cilium, a signaling organelle projecting from the surface of vertebrate cells. Consequently, gain of EZH2 function promotes loss of primary cilia in benign melanocytic lesions. In contrast, blockade of EZH2 activity evokes ciliogenesis and cilia-dependent growth inhibition in malignant melanoma. Finally, we demonstrate that loss of cilia enhances pro-tumorigenic WNT/β-catenin signaling and is itself sufficient to drive metastatic melanoma in benign cells. Thus, primary cilia deconstruction is a key process in EZH2-driven melanomagenesis.

2019-04-04 | GSE112677 | GEO

Integrative analyses of rhabdoid tumors across all anatomical sites reveal subgroups with possible immune modulation through epigenetic dysregulation

Project description:Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are pediatric cancers driven by SMARCB1 loss. To understand biological relationships between MRTs and ATRTs, we performed integrative data analyses of 140 MRTs and 161 ATRTs, and detected features conserved between MRTs and the MYC subgroup of ATRTs, including global DNA hypomethylation and over-expression of HOX and mesenchymal development genes, thereby distinguishing them from other ATRT subgroups that exhibit neural-like features. Our analyses revealed five DNA-methylation subgroups associated with distinct anatomical sites, SMARCB1 alteration patterns, and distinct gene-expression and enhancer profiles. We also report on RT subgroups with expression patterns indicative of both increased immune infiltration and expression of immune checkpoint genes, which were confirmed using immunohistochemical techniques.

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SMARCB1 loss induces druggable cyclin D1 deficiency via upregulation of MIR17HG in atypical teratoid rhabdoid tumors

Project description:Atypical teratoid rhabdoid tumor (ATRT) is a fatal pediatric malignancy of the central neural system lacking effective treatment options. It belongs to rhabdoid tumor family usually caused by biallelic inactivation of SMARCB1, encoding a key subunit of SWI/SNF chromatin remodelling complexes. Previous studies proposed that SMARCB1 loss drives rhabdoid tumor by promoting cell cycle through activating transcription of cyclin D1 while suppressing p16. However, low cyclin D1 protein expression is observed in most ATRT patient tumors. The underlying mechanism and therapeutic implication of this molecular trait remain unknown. Here, we show that SMARCB1 loss in ATRT leads to the reduction of cyclin D1 expression by upregulating MIR17HG, a microRNA (miRNA) cluster known to generate multiple miRNAs targeting CCND1. Furthermore, we find that this cyclin D1 deficiency in ATRT results in marked in vitro and in vivo sensitivity to the CDK4/6 inhibitor palbociclib as a single agent. Our study identifies a novel genetic interaction between SMARCB1 and MIR17HG in regulating cyclin D1 in ATRT and suggests a rationale to treat ATRT patients with FDA-approved CDK4/6 inhibitors.

2020-06-08 | GSE147851 | GEO

Transcription profiling of Xenopus epithelial explants injected with the intracellular domain of Notch (ICD) to block the formation of multi-ciliate cells, either alone or along with FoxJ1

Project description:Analysis of epithelial explants injected with the intracellular domain of Notch (ICD) to block the formation of multi-ciliate cells, either alone or along with FoxJ1. FoxJ1 misexpression leads to the induction fo ectopic cilia in Xenopus laevis epithelia. Results show which genes are affected by FoxJ1 during the induction of ectopic cilia. Ciliated cells that produce a leftward fluid flow have been proposed to mediate left-right patterning in many vertebrate embryos. These cilia combine features of primary sensory and motile cilia, but how such cilia are specified is unknown. We address this issue by analyzing the Xenopus and Zebrafish homologs of FoxJ1, a forkhead transcription factor necessary for ciliogenesis in multi-ciliate cells of the mouse. We show that the cilia that underlie left-right patterning on the Xenopus gastrocoel roof plate (GRP) and Zebrafish Kupfferâs vesicle (KV) are severely shortened or fail to form in FoxJ1 morphants. We also show that misexpressing XFoxJ1 is sufficient to induce ectopic GRP-like cilia formation in frog embryos. Microarray analysis indicates that XFoxJ1 induces the formation of cilia by upregulating the expression of motile cilia genes. These results indicate that FoxJ1 is a critical determinant in specifying cilia used in left-right patterning. Experiment Overall Design: 2-cell stage Xenopus embryos were injected with synthetic mRNA encoding ICD alone or along with FoxJ1. At stage 9/10 the presumptive ectoderm was cut off the embryo and cultured on a fibronectin coated coverslip. At stage 22 RNA was harvested from explants and used as the starting material for arrays.

2008-10-25 | E-GEOD-12613 | biostudies-arrayexpress

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