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ATR Mutations Promote the Growth of Melenama Tumor by Modulating the Immune Microenvironment

ABSTRACT: ATR Mutations Promote the Growth of Melenama Tumor by Modulating the Immune Microenvironment

PROVIDER: PRJNA369212 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5217290_1.fastq.gz	Fastqsanger.gz
	SRR5217290_2.fastq.gz	Fastqsanger.gz
	SRR5217300_1.fastq.gz	Fastqsanger.gz
	SRR5217300_2.fastq.gz	Fastqsanger.gz
	SRR5217310_1.fastq.gz	Fastqsanger.gz

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ATR Mutations Promote the Growth of Melenama Tumor by Modulating the Immune Microenvironment [tumor]

Project description:Melanomas accumulate a high burden of mutations that could potentially generate neoantigens, yet these tumors are still able to suppress the immune response in order to facilitate their continued growth. In this study, we identify subsets of human melanoma tumors that have partial loss of function mutations in ATR, a kinase that recognizes and repairs UV-induced DNA damage and is required for cellular proliferation. ATR mutant tumors exhibit both the accumulation of multiple mutations and the altered expression of inflammatory genes, resulting in decreased T-cell recruitment and increased recruitment of macrophages known to spur tumor invasion. Taken together, these studies identify a novel mechanism by which melanoma cells modulate the immune microenvironment to allow continued tumor growth.

2017-01-31 | GSE94264 | GEO

ATR Mutations Promote the Growth of Melenama Tumor by Modulating the Immune Microenvironment [skin]

2017-01-31 | GSE94263 | GEO

ATR Mutations Promote the Growth of Melanoma Tumors by Modulating the Immune Microenvironment.

Project description:Melanomas accumulate a high burden of mutations that could potentially generate neoantigens, yet somehow suppress the immune response to facilitate continued growth. In this study, we identify a subset of human melanomas that have loss-of-function mutations in ATR, a kinase that recognizes and repairs UV-induced DNA damage and is required for cellular proliferation. ATR mutant tumors exhibit both the accumulation of multiple mutations and the altered expression of inflammatory genes, resulting in decreased T cell recruitment and increased recruitment of macrophages known to spur tumor invasion. Taken together, these studies identify a mechanism by which melanoma cells modulate the immune microenvironment to promote continued growth.

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ATR Mutations Promote the Growth of Melenama Tumor by Modulating the Immune Microenvironment

Project description:This SuperSeries is composed of the SubSeries listed below.

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Mus musculus

Project description:ATR Mutations Promote the Growth of Melenama Tumor by Modulating the Immune Microenvironment [tumor]

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Mus musculus

Project description:ATR Mutations Promote the Growth of Melenama Tumor by Modulating the Immune Microenvironment [skin]

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SETD2 loss and ATR inhibition synergistically promote cGAS signaling and immunotherapy response in renal cell carcinoma

Project description:Immune checkpoint blockade (ICB) demonstrates durable clinical benefit only in a minority of renal cell carcinoma (RCC) patients. Identifying molecular features that determine response and developing approaches to enhance the response remain an urgent clinical need. Here we found that, in multiple RCC cell lines, targeting the ATR-CHK1 axis with pharmacological inhibitors increased cytosolic DNA accumulation, activated the cGAS-IRF3-dependent cytosolic DNA sensing pathway, and resulted in the inflammatory cytokine expression. SETD2 mutated RCC cell lines or tumor samples were associated with preferential ATR-CHK1 activation over ATM-CHK2 activation. SETD2 knockdown promoted the cytosolic DNA sensing pathway and conferred greater sensitivity in response to ATR-CHK1 inhibition. In murine Renca tumors, Setd2 knockdown and ATR inhibitor VE822 synergistically promoted cytosolic DNA sensing pathway, immune cell infiltration, and immune checkpoint protein expression. Setd2 deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or in combination with VE822 than Setd2 proficient tumors. SETD2 mutations were associated with a higher response rate and prolonged overall survival in ICB-treated RCC patients, but not in non-ICB-treated RCC patients. This study provides a mechanism-based guidance to develop more personalized combination therapy regimens for RCC patients with SETD2 mutations.

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Atr maintains chromosomal integrity during postnatal cerebellar neurogenesis [Affymetrix]

Project description:Microcephaly and medulloblastoma result from mutations that compromise genomic stability. We report that Atr, which is mutated in the microcephalic disorder Seckel syndrome, is required to maintain chromosomal integrity during postnatal cerebellar neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis, and cerebellar hypoplasia. Co-deletions of either Bax and Bak or p53 prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. Atr-deficient CGNPs showed impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to Atr-deficient proliferation was p53-driven. Acute Atr inhibition in vivo by nanoparticle-formulated VE-822 reproduced the disruptions seen with Atr deletion. Our data show that p53-driven apoptosis and senescence, and non-apoptotic cell death redundantly limit growth in Atr-deficient progenitors. These overlapping mechanisms that suppress growth in Atr-disrupted CGNPs may be exploited for treatment of CGNP-derived medulloblastoma using Atr inhibition.

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Atr maintains chromosomal integrity during postnatal cerebellar neurogenesis [RNA-Seq]

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Transcription profiling of shoot apices from Arabidopsis wild type, teb, atr, and teb atr mutant plants

Project description:Global gene expression patterns were compared among wild-type Col-0, teb, atr, teb atr of A. thaliana using shoot apices.

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