SETD2 loss and ATR inhibition synergistically promote cGAS signaling and immunotherapy response in renal cell carcinoma
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE234732 | GEO | 2023/07/25
REPOSITORIES: GEO
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Project description:Three-dimensional (3D) organoids provide a new way to model various diseases, including cancer. We made use of recently developed kidney-organ-primordia tissue-engineering technologies to create novel renal organoids for cancer gene discovery. We then tested whether our novel assays can be used to examine kidney cancer development. First, we identified the transcriptomic profiles of quiescent embryonic mouse metanephric mesenchyme (MM) and of MM in which the nephrogenesis program had been induced ex vivo. The transcriptome profiles were then compared to the profiles of tumor biopsies from renal cell carcinoma (RCC) patients, and control samples from the same kidneys. Certain signature genes were identified that correlated in the developmentally induced MM and RCC, including components of the caveolar-mediated endocytosis signaling pathway. An efficient siRNA-mediated knockdown (KD) of Bnip3, Gsn, Lgals3, Pax8, Cav1, Egfr or Itgb2 gene expression was achieved in mouse RCC (Renca) cells. The live-cell imaging analysis revealed inhibition of cell migration and cell viability in the gene-KD Renca cells in comparison to Renca controls. Upon siRNA treatment, the transwell invasion capacity of Renca cells was also inhibited. Finally, we mixed the nephron progenitors with yellow fluorescent protein (YFP)-expressing Renca cells to establish chimera organoids. Strikingly, we found that the Bnip3-, Cav1- and Gsn-KD Renca-YFP+ cells as a chimera with the MM in 3D organoid rescued, in part, the RCC-mediated inhibition of the nephrogenesis program during epithelial tubules formation. Altogether, our research indicates that comparing renal ontogenesis control genes to the genes involved in kidney cancer may provide new growth-associated gene screens and that 3D RCC-MM chimera organoids can serve as a novel model with which to investigate the behavioral roles of cancer cells within the context of emergent complex tissue structures.
2017-12-05 | GSE107657 | GEO
Project description:ARID1A is a core protein subunit of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex and among the most frequently mutated tumor suppressors in human cancers. Immune checkpoint blockade (ICB) clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to ICB in a number of solid tumor types in a manner that is independent of microsatellite instability. However, the molecular mechanisms that promote improved ICB response in ARID1A mutant tumors remain incompletely understood. We developed ARID1A deficient murine tumor models that exhibit anti-tumor immune phenotypes such as increased CD8+ T cell infiltration and activation observed in ARID1A mutant human cancers. Leveraging these tumor models and public transcriptomic datasets, we discovered that ARID1A deficient cancers display upregulation of an immunogenic interferon (IFN) gene expression signature, including genes known to mediate T/NK cell recruitment and activation. ARID1A loss increased cytosolic single stranded DNA (ssDNA) and cytosolic RNA:DNA hybrids which are known to induce IFN via viral mimicry and were associated with increased presence of R-Loops as a result of transcription-replication conflicts during DNA replication. Accordingly, overexpression of the R-Loop resolving enzyme, RNaseH2B, or the cytosolic DNase, TREX1, restores ARID1A loss induced interferon stimulated gene (ISG) upregulation to control levels. Furthermore, we demonstrate that the ARID1A-IFN gene expression signature and anti-tumor immunity is driven by STING dependent cytosolic DNA sensing and Type I IFN, which is requirement for the improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings represent a novel molecular mechanism underlying anti-tumor immunity in ARID1A-mutant cancers and may have translational utility in improving patient selection for ICB.
2024-04-06 | GSE217803 | GEO
Project description:ARID1A is a core protein subunit of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex and among the most frequently mutated tumor suppressors in human cancers. Immune checkpoint blockade (ICB) clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to ICB in a number of solid tumor types in a manner that is independent of microsatellite instability. However, the molecular mechanisms that promote improved ICB response in ARID1A mutant tumors remain incompletely understood. We developed ARID1A deficient murine tumor models that exhibit anti-tumor immune phenotypes such as increased CD8+ T cell infiltration and activation observed in ARID1A mutant human cancers. Leveraging these tumor models and public transcriptomic datasets, we discovered that ARID1A deficient cancers display upregulation of an immunogenic interferon (IFN) gene expression signature, including genes known to mediate T/NK cell recruitment and activation. ARID1A loss increased cytosolic single stranded DNA (ssDNA) and cytosolic RNA:DNA hybrids which are known to induce IFN via viral mimicry and were associated with increased presence of R-Loops as a result of transcription-replication conflicts during DNA replication. Accordingly, overexpression of the R-Loop resolving enzyme, RNaseH2B, or the cytosolic DNase, TREX1, restores ARID1A loss induced interferon stimulated gene (ISG) upregulation to control levels. Furthermore, we demonstrate that the ARID1A-IFN gene expression signature and anti-tumor immunity is driven by STING dependent cytosolic DNA sensing and Type I IFN, which is requirement for the improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings represent a novel molecular mechanism underlying anti-tumor immunity in ARID1A-mutant cancers and may have translational utility in improving patient selection for ICB.
2024-04-06 | GSE217806 | GEO
Project description:ARID1A is a core protein subunit of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex and among the most frequently mutated tumor suppressors in human cancers. Immune checkpoint blockade (ICB) clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to ICB in a number of solid tumor types in a manner that is independent of microsatellite instability. However, the molecular mechanisms that promote improved ICB response in ARID1A mutant tumors remain incompletely understood. We developed ARID1A deficient murine tumor models that exhibit anti-tumor immune phenotypes such as increased CD8+ T cell infiltration and activation observed in ARID1A mutant human cancers. Leveraging these tumor models and public transcriptomic datasets, we discovered that ARID1A deficient cancers display upregulation of an immunogenic interferon (IFN) gene expression signature, including genes known to mediate T/NK cell recruitment and activation. ARID1A loss increased cytosolic single stranded DNA (ssDNA) and cytosolic RNA:DNA hybrids which are known to induce IFN via viral mimicry and were associated with increased presence of R-Loops as a result of transcription-replication conflicts during DNA replication. Accordingly, overexpression of the R-Loop resolving enzyme, RNaseH2B, or the cytosolic DNase, TREX1, restores ARID1A loss induced interferon stimulated gene (ISG) upregulation to control levels. Furthermore, we demonstrate that the ARID1A-IFN gene expression signature and anti-tumor immunity is driven by STING dependent cytosolic DNA sensing and Type I IFN, which is requirement for the improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings represent a novel molecular mechanism underlying anti-tumor immunity in ARID1A-mutant cancers and may have translational utility in improving patient selection for ICB.
2024-04-06 | GSE217805 | GEO
Project description:ARID1A is a core protein subunit of the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex and among the most frequently mutated tumor suppressors in human cancers. Immune checkpoint blockade (ICB) clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to ICB in a number of solid tumor types in a manner that is independent of microsatellite instability. However, the molecular mechanisms that promote improved ICB response in ARID1A mutant tumors remain incompletely understood. We developed ARID1A deficient murine tumor models that exhibit anti-tumor immune phenotypes such as increased CD8+ T cell infiltration and activation observed in ARID1A mutant human cancers. Leveraging these tumor models and public transcriptomic datasets, we discovered that ARID1A deficient cancers display upregulation of an immunogenic interferon (IFN) gene expression signature, including genes known to mediate T/NK cell recruitment and activation. ARID1A loss increased cytosolic single stranded DNA (ssDNA) and cytosolic RNA:DNA hybrids which are known to induce IFN via viral mimicry and were associated with increased presence of R-Loops as a result of transcription-replication conflicts during DNA replication. Accordingly, overexpression of the R-Loop resolving enzyme, RNaseH2B, or the cytosolic DNase, TREX1, restores ARID1A loss induced interferon stimulated gene (ISG) upregulation to control levels. Furthermore, we demonstrate that the ARID1A-IFN gene expression signature and anti-tumor immunity is driven by STING dependent cytosolic DNA sensing and Type I IFN, which is requirement for the improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings represent a novel molecular mechanism underlying anti-tumor immunity in ARID1A-mutant cancers and may have translational utility in improving patient selection for ICB.
2024-04-06 | GSE217804 | GEO
Project description:Finding the downstream miRNAs of SETD2 in the renal cell carcinoma cell line the coordinated expression of SETD2-miRNAs-MAPK/JNK may be predictive of poor prognostic in patients with RCC. Our findings also emphasize the therapeutic potential of MAP4K4 in RCC therapy and support the development of an effective therapeutic strategy to target MAP4K4 by molecularly targeted approaches
2019-07-31 | GSE135105 | GEO
Project description:Excessive genomic instability coupled with abnormalities in DNA repair pathways induce high levels of “replication stress” when cancer cells propagate. Rather than hampering cancer cell proliferation, novel treatment strategies are turning their attention toward targeting cell cycle checkpoint kinases (such as ATR, CHK1, WEE1 and others) along the DNA damage response and replicative stress response pathways, thereby allowing unrepaired DNA damage to be carried forward towards mitotic catastrophe and apoptosis. The selective inhibitor of ATR kinase elimusertib (BAY 1895344), has demonstrated preclinical and clinical monotherapy activity; however, reliable predictive biomarkers of treatment benefit are still lacking. In this study, using gene expression profiling of 24 cell lines from different cancer types and in a panel of ovarian cancer cell lines, we found that nuclear-specific enrichment of checkpoint kinase 1 (CHK1) correlated with increased sensitivity to elimusertib. Using an advanced multispectral imaging system in subsequent cell line-derived xenograft specimens, we showed a trend between nuclear phosphorylated-CHK1 (pCHK1) staining and increased sensitivity to the ATR inhibitor elimusertib, indicating the potential value of pCHK1 expression as a predictive biomarker of ATR inhibitor sensitivity.
2022-11-09 | GSE217579 | GEO
Project description:The aim of the present study was to investigate the potential role of HIF-2a in regulating RCC susceptibility to natural killer (NK) cell-mediated killing. We demonstrated that the RCC cell line 786-O with mutated VHL was resistant to NK-mediated lysis as compared to the VHL corrected cell line (WT7). This resistance was independent of immunological synapse formation and NK ligand expression but was found to be reliant on HIF-2a stabilization in 786-0 cells. In order to elucidate the molecular basis of HIF-2a-induced impairment of NK-mediated killing, we performed global gene analysis using DNA microarray. Three candidate genes (ANGPTL4, ADM and ITPR1) were selected on the basis of their fold change and their involvement in cell death and survival. SiRNA targeting of these genes revealed that only ITPR1 silencing resulted in a significant increase of 786-O susceptibility to NK-mediated lysis. Using gene silencing of HIF2-a and chromatin immunoprecipitation assay, we showed for the first time that ITPR1 was a direct novel target of HIF2-a. Notably, a strong and significant correlation was found between ITPR1and HIF2-a staining in RCC patients. Transcriptional profiling of ITPR1silenced RCC cells indicated that several important genes involved in cell survival and apoptosis were differentially regulated. Using ITPR1 silenced Renca cells, we further found that ITPR1 was involved in the control of tumor progression. Moreover ITPR1 targeting combined with NK depletion significantly enhanced tumor growth as compared to ITPR1 knocked down Renca xenografts. Our data provide insights into the link between HIF-2a, ITPR1-related pathway and natural immunity and suggest a role of the HIF2/ITPR1 axis in regulating RCC cell survival.
2014-01-11 | E-MTAB-1802 | biostudies-arrayexpress
Project description:Recently, we reported that expression of endogenous retroviruses (ERVs), a class of transposable element, is associated with response to immune checkpoint blockade (ICB) in renal cell carcinoma (RCC). Aberrant expression of ERVs can activate host antiviral responses, as well as produce neoantigens. ERV expression is repressed by DNA methylation and can be activated by DNA hypomethylating agents. Here, we investigate whether Decitabine, a DNA hypomethylating agent, can activate ERV expression and host antiviral defenses in RCC to potentially enhance response to ICB. Decitabine induced expression of ERV3-2 and ERV4700 in RCC cells lines, which was accompanied by activation of host antiviral defense genes and increased secretion of inflammatory cytokines. We validated this effect in primary human RCC cell lines. Knockout of RIG-I and MDA5 dsRNA sensors attenuated activation of antiviral responses associated with Decitabine treatment, and RIG-I and MDA5 immunoprecipitations showed increased ERV binding in RCC cells treated with Decitabine. Bioinformatic analysis of RNAseq data showed the Decitabine-induced gene signature could be associated with increased CD8 infiltration and response to ICB. Conditioned media from Decitabine treated RCC cells was capable of inducing host anti-viral defense in naïve RCC cells and could modestly improve activation of T-cells from healthy donors. Further, conditioned media from RCC cells treated with Decitabine significantly enhanced T-cell migration. In a small retrospective cohort of metastatic RCC patients treated with single-agent PD-1/PD-L1 blockade, activation of some host antiviral defense genes was significantly higher in responders compared with nonresponders. Thus, modulation of ERV expression by Decitabine to activate host antiviral defenses could represent a novel therapeutic strategy to enhance RCC patient response to immune checkpoint blockade.
2020-06-01 | GSE142381 | GEO
Project description:Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, ICB alone has demonstrated only benefit in a small subset of patients with breast cancer. We here reported that the tumoral cytosolic ssDNA is associated with tumor-infiltrating lymphocyte in patients with triple negative breast cancer. TREX1 deficiency triggered a STING-independent innate immune response via DDX3X. Cytosolic ssDNA accumulation in tumors due to TREX1 deletion is sufficient to drastically improve the efficacy of ICB.
2023-09-28 | GSE244296 | GEO