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E-MTAB-7497

ABSTRACT: TP53 is a master regulator of proteostasis in SMARCB1-deficient malignant rhabdoid tumors

PROVIDER: E-MTAB-7497 | ExpressionAtlas | 2019-03-20

REPOSITORIES: ExpressionAtlas

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			Action	DRS
	E-MTAB-7497-analysis-methods.tsv	Tabular
	E-MTAB-7497-atlasExperimentSummary.Rdata	Rdata
	E-MTAB-7497-configuration.xml	Xml
	E-MTAB-7497-percentile-ranks.tsv	Tabular
	E-MTAB-7497.condensed-sdrf.tsv	Tabular

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Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

Project description:SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development. Two cancer cell lines, 167 and 365, derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice were re-infected with a retro-viral vector for Smarcb1 re-expression or an empty retro-viral vector as control. Total-RNA was collected 3 days post infection so as to enrich for direct targets of Smarcb1 transcriptionaly regulated genes

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Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

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Mouse Smarcb1-deficient models recapitulate subtypes of human rhabdoid tumors.

Project description:Rhabdoid Tumors (RT) are highly aggressive tumors that are frequently localized in the central nervous system (CNS) where they are termed atypical teratoid and rhabdoid tumors (ATRT). We generated conditional Smarcb1-deficient mouse model leads to CNS Smarcb1-deficient tumors. We used microarrays to compared gene expression profilings of various human and mouse tumors. Our data demonstrate that the Smarcb1-deficient mouse model recapitulates the diversity of human RT.

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Project description:Loss of function mutations in SMARCB1 are prevalent in pediatric atypical teratoid rhabdoid tumors (ATRTs) and confer an oncogenic dependency on EZH2, providing a compelling rationale for treating these genetically defined cancers via EZH2 inhibition (EZH2i). EZH2i results in tumor regression in SMARCB1-deficient tumors in preclinical studies, but the molecular mechanism has not been fully elucidated. Here we found that the sensitivity of SMARCB1-deficient tumors to EZH2i is associated with the viral mimicry response that depends on both double-stranded RNA (dsRNA) and cytoplasmic DNA sensing pathways. Unlike other epigenetic therapies targeting transcriptional repressors, viral mimicry by EZH2i in SMARCB1-deficient tumors is not triggered by crypt initiation of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, we found that interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a positive feedback loop whereby interferon response leads to dsRNA formation from intronic ISGs and activation of viral mimicry. Moreover, EZH2i in ATRT cells also enhances the expression of full-length LINE-1 elements, leading to genomic instability and cGAS/STING response in a process dependent on reverse transcriptase activity. Supporting this mechanism, co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.

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Project description:The multi-subunit ATP-dependent chromatin remodeling complex BAF ('mammalian SWI/SNF complex') regulates DNA accessibility during cell fate transitions and functions as a context-dependent tumor suppressor. SMARCB1, as a one of the component of BAF complex, was first found to be biallelically inactivated in ~98% of all malignant rhabdoid tumors (MRT), aggressive pediatric tumors that can occur cranially or extracranially. To examine the mechanisms through which inactivation of SMARCB1 drives malignant rhabdoid tumorigenesis, we conducted RNAseq studies in BT-12 cells reconstituted with either WT or M4 mutant (an in-frame deletion (185-193D) was identified from tumor patient) SMARCB1. These results indicate that loss of SMARCB1 promotes cell proliferation but also impairs cell adhesion and migration, consistent with the hypothesis that SMARCB1 exerts its tumor suppressive function predominantly by inhibiting proliferation. We applied the RNA-Seq to provide the transcriptomic profiling of BT-12 cell lines without or with stable expression of SMARCB1.

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Embryonic signature distinguishes pediatric and adult rhabdoid tumors from other SMARCB1-deficient cancers

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