ORCID Profile
0000-0002-2578-8872
Current Organisation
Remix Therapeutics
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Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539128.V1
Abstract: Loss of Arid1a or Smarcb1 promotes increased accessibility to binding motifs for non-canonical BAF complexes.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22535665
Abstract: supplementary tables and material and methods
Publisher: Cold Spring Harbor Laboratory
Date: 29-05-2022
DOI: 10.1101/2022.05.28.493429
Abstract: Polycomb Repressive Complex 2 (PRC2) establishes and maintains di- and tri-methylation at histone 3 at lysine 27 (H3K27me2/3) in the genome and plays oncogenic and tumor suppressor roles in context-dependent cancer pathogenesis. While there is clinical success of therapeutically targeting PRC2 core component, EZH2, in PRC2-dependent cancers (e.g., follicular lymphoma, epithelioid sarcoma), it remains an unmet therapeutic bottleneck in PRC2-inactivated cancer. Biallelic inactivating mutations in PRC2 core components are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive subtype of sarcoma with poor prognosis and no effective targeted therapeutics. Using a custom RNAi-based drop out screen, we observed that PRC2-inactivation is synthetic lethal with DNA methyltransferase 1 (DNMT1) downregulation we further observed that small molecule DNMT inhibitors (DNMTis) resulted in enhanced cytotoxicity and antitumor response in PRC2-loss cancer context in vitro and in vivo . Mechanistically, DNMTi-mediated de-repression of retrotransposons (e.g., endogenous retroviral elements (ERVs)/LTR, LINE, SINE) and gene targets is partly restricted by PRC2, which potentially contributes to limited therapeutic activity in PRC2-wild-type (wt) cancer context. In contrast, DNMTi treatment synergizes with PRC2 inactivation and cooperatively lifies the expression of retrotransposons (e.g., ERV/LTR, LINE, SINE), and subsequent viral mimicry response that promotes robust cell death in part through PKR-dependent double stranded-RNA (dsRNA) sensing. Collectively, our observations posit DNA methylation as a safeguard against anti-tumorigenic cell fate decisions in the context of PRC2-inactivation to promote cancer pathogenesis. Further, they identified a novel targeted therapeutic strategy in PRC2-inactivated MPNST and delineated the PRC2-inactivated cancer context for future preclinical exploration and clinical investigation of DNMT1-targeted therapies in cancer. PRC2-inactivation drives oncogenesis in various cancers but therapeutically targeting PRC2-loss has remained challenging. Here we show that PRC2 inactivating mutations sets up a tumor context-specific liability for synthetic lethal interaction with genetic and therapeutic inhibition of DNMT1. DNMT1 inhibitor-induced cytotoxicity in PRC2-loss cancer context is accompanied by innate immune signaling signature through PKR-mediated sensing of endogenous retrotransposons. These observations posit a therapeutic window via direct anti-tumor effect by DNMT1 inhibitors in PRC2-loss cancers, and point to potentials to be combined with innovative immunotherapeutic strategies to capitalize on innate immune signaling activation.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539092.V1
Abstract: SWISNF mutations in thyroid cancers
Publisher: American Association for Cancer Research (AACR)
Date: 11-2020
DOI: 10.1158/2159-8290.CD-20-0026
Abstract: Expression of PRMT5 and E2F targets is increased in JAK2V617F+ MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2V617F/MPLW515L MPN models and primary s les. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated. This article is highlighted in the In This Issue feature, p. 1611
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539083.V1
Abstract: List of Primers for qRT-PCR
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539101
Abstract: Impact of acute MAPK blockade on chromatin accessibility in TBraf and TBraf/Swi-Snf deficient tumors.
Publisher: American Society for Clinical Investigation
Date: 15-11-2018
Publisher: Springer Science and Business Media LLC
Date: 08-05-2017
DOI: 10.1038/S41598-017-01617-3
Abstract: RNA-sequencing has become the gold standard for whole-transcriptome gene expression quantification. Multiple algorithms have been developed to derive gene counts from sequencing reads. While a number of benchmarking studies have been conducted, the question remains how in idual methods perform at accurately quantifying gene expression levels from RNA-sequencing reads. We performed an independent benchmarking study using RNA-sequencing data from the well established MAQCA and MAQCB reference s les. RNA-sequencing reads were processed using five workflows (Tophat-HTSeq, Tophat-Cufflinks, STAR-HTSeq, Kallisto and Salmon) and resulting gene expression measurements were compared to expression data generated by wet-lab validated qPCR assays for all protein coding genes. All methods showed high gene expression correlations with qPCR data. When comparing gene expression fold changes between MAQCA and MAQCB s les, about 85% of the genes showed consistent results between RNA-sequencing and qPCR data. Of note, each method revealed a small but specific gene set with inconsistent expression measurements. A significant proportion of these method-specific inconsistent genes were reproducibly identified in independent datasets. These genes were typically smaller, had fewer exons, and were lower expressed compared to genes with consistent expression measurements. We propose that careful validation is warranted when evaluating RNA-seq based expression profiles for this specific gene set.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539104
Abstract: Effects of BrafV600E on thyroid differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539125.V1
Abstract: Smarcb1 loss is associated with active enhancer romoter marks at CTCF motif.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539107
Abstract: Impact of Arid1a, Arid2 and Smarcb1 loss on thyroid lineage TF expression and chromatin accessibility.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.C.6547909.V1
Abstract: Abstract We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells, and PRMT5 inhibition potently reduced MPN cell proliferation i ex vivo /i . PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis, and splenomegaly in a model of JAK2 sup V617F+ /sup polycythemia vera and leukocyte and platelet counts, hepatosplenomegaly, and fibrosis in the MPL sup W515L /sup model of myelofibrosis. Dual targeting of JAK and PRMT5 was superior to JAK or PRMT5 inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis i in vivo. /i PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell-cycle arrest, and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN. Significance: Expression of PRMT5 and E2F targets is increased in JAK2 sup V617F+ /sup MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2 sup V617F /sup /MPL sup W515L /sup MPN models and primary s les. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated. i This article is highlighted in the In This Issue feature, p. 1611 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22535668
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.C.6548987.V1
Abstract: Abstract Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of i Arid1a, Arid2 /i , or i Smarcb1 /i in mouse BRAF sup V600E /sup -mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAF sup V600E /sup -mutant mouse papillary thyroid cancers have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid-differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition. Loss of in idual SWI/SNF subunits in BRAF tumors leads to a repressive chromatin state that cannot be reversed by MAPK pathway blockade, rendering them insensitive to its redifferentiation effects. Our results show that SWI/SNF complexes are central to the maintenance of differentiated function in thyroid cancers, and their loss confers radioiodine refractoriness and resistance to MAPK inhibitor–based redifferentiation therapies. Significance: Reprogramming cancer differentiation confers therapeutic benefit in various disease contexts. Oncogenic BRAF silences genes required for radioiodine responsiveness in thyroid cancer. Mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage specification genes in i BRAF /i -mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade. i This article is highlighted in the In This Issue feature, p. 995 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539104.V1
Abstract: Effects of BrafV600E on thyroid differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540903
Abstract: Supplementary Data from PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540900
Abstract: Supplementary Data from PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549502
Abstract: Abstract Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation lifies DNMT inhibitor–mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)–dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy. Significance: PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context–specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-22-0733" target="_blank" See related commentary by Guil and Esteller, p. 2020 /a . /i i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-9-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2007 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539119.V1
Abstract: Schema of redifferentiation trials.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539110
Abstract: Impact of Swi/Snf subunit loss on serum TSH levels and chromatin landscape.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539113
Abstract: Validation of tumor derived TBraf, TBraf/A1a, TBraf/A2 and TBraf/Sb1 cell lines.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539122.V1
Abstract: Restoration of Nis (SLC5A5) expression upon MEK inhibition is attenuated in Braf-tumors with Swi/Snf loss.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539116
Abstract: Loss of Arid1a or Smarcb1 in the context of endogenous BrafV600E expression promotes tumor growth in mice.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22535668.V1
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539086.V1
Abstract: Significance of ATAC-RNA concordance
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549502.V1
Abstract: Abstract Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation lifies DNMT inhibitor–mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)–dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy. Significance: PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context–specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-22-0733" target="_blank" See related commentary by Guil and Esteller, p. 2020 /a . /i i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-9-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2007 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539119
Abstract: Schema of redifferentiation trials.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539101.V1
Abstract: Impact of acute MAPK blockade on chromatin accessibility in TBraf and TBraf/Swi-Snf deficient tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 31-10-2017
DOI: 10.1158/1541-7786.MCR-17-0332
Abstract: Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence of any cancer, along with poor five-year survival rates. Barrett's esophagus (BE) is the main risk factor for EAC however, the mechanisms driving EAC development remain poorly understood. Here, transcriptomic profiling was performed using RNA-sequencing (RNA-seq) on premalignant and malignant Barrett's tissues to better understand this disease. Machine-learning and network analysis methods were applied to discover novel driver genes for EAC development. Identified gene expression signatures for the distinction of EAC from BE were validated in separate datasets. An extensive analysis of the noncoding RNA (ncRNA) landscape was performed to determine the involvement of novel transcriptomic elements in Barrett's disease and EAC. Finally, transcriptomic mutational investigation of genes that are recurrently mutated in EAC was performed. Through these approaches, novel driver genes were discovered for EAC, which involved key cell cycle and DNA repair genes, such as BRCA1 and PRKDC. A novel 4-gene signature (CTSL, COL17A1, KLF4, and E2F3) was identified, externally validated, and shown to provide excellent distinction of EAC from BE. Furthermore, expression changes were observed in 685 long noncoding RNAs (lncRNA) and a systematic dysregulation of repeat elements across different stages of Barrett's disease, with wide-ranging downregulation of Alu elements in EAC. Mutational investigation revealed distinct pathways activated between EAC tissues with or without TP53 mutations compared with Barrett's disease. In summary, transcriptome sequencing revealed altered expression of numerous novel elements, processes, and networks in EAC and premalignant BE. Implications: This study identified opportunities to improve early detection and treatment of patients with BE and esophageal adenocarcinoma. Mol Cancer Res 15(11) 1558–69. ©2017 AACR.
Publisher: Frontiers Media SA
Date: 10-2015
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2FO30075C
Abstract: Polyphenolic compounds derived mainly from plant products have demonstrated neuroprotective properties in a number of experimental settings. Such protective effects have often been ascribed to antioxidant capacity, but specific augmentation of other cellular defences and direct interactions with neurotoxic proteins have also been demonstrated. With an emphasis on neurodegenerative conditions, such as Alzheimer's disease, we highlight recent findings on the neuroprotection ascribed to bioactive polyphenols capable of directly interfering with the Alzheimer's disease hallmark toxic β-amyloid protein (Aβ), thereby inhibiting fibril and aggregate formation. This includes compounds such as the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) and the phytoalexin resveratrol. Targeted studies on the biomolecular interactions between dietary polyphenolics and Aβ have not only improved our understanding of the pathogenic role of β-amyloid, but also offer fundamentally novel treatment options for Alzheimer's disease and potentially other amyloidoses.
Publisher: Springer Science and Business Media LLC
Date: 05-11-2019
DOI: 10.1038/S41467-019-12971-3
Abstract: The majority of patients with neuroblastoma due to MYCN oncogene lification and consequent N-Myc oncoprotein over-expression die of the disease. Here our analyses of RNA sequencing data identify the long noncoding RNA lncNB1 as one of the transcripts most over-expressed in MYCN - lified, compared with MYCN -non- lified, human neuroblastoma cells and also the most over-expressed in neuroblastoma compared with all other cancers. lncNB1 binds to the ribosomal protein RPL35 to enhance E2F1 protein synthesis, leading to DEPDC1B gene transcription. The GTPase-activating protein DEPDC1B induces ERK protein phosphorylation and N-Myc protein stabilization. Importantly, lncNB1 knockdown abolishes neuroblastoma cell clonogenic capacity in vitro and leads to neuroblastoma tumor regression in mice, while high levels of lncNB1 and RPL35 in human neuroblastoma tissues predict poor patient prognosis. This study therefore identifies lncNB1 and its binding protein RPL35 as key factors for promoting E2F1 protein synthesis, N-Myc protein stability and N-Myc-driven oncogenesis, and as therapeutic targets.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539113.V1
Abstract: Validation of tumor derived TBraf, TBraf/A1a, TBraf/A2 and TBraf/Sb1 cell lines.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2016
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539092
Abstract: SWISNF mutations in thyroid cancers
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539098.V1
Abstract: Effects of MEK inhibition on chromatin accessibility at thyroid lineage TF targets and at key MAPK downstream effectors in TBraf and TBraf/Swi-Snf deficient tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539116.V1
Abstract: Loss of Arid1a or Smarcb1 in the context of endogenous BrafV600E expression promotes tumor growth in mice.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539083
Abstract: List of Primers for qRT-PCR
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539086
Abstract: Significance of ATAC-RNA concordance
Publisher: American Society for Clinical Investigation
Date: 09-2022
DOI: 10.1172/JCI153437
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539122
Abstract: Restoration of Nis (SLC5A5) expression upon MEK inhibition is attenuated in Braf-tumors with Swi/Snf loss.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22535665.V1
Abstract: supplementary tables and material and methods
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539125
Abstract: Smarcb1 loss is associated with active enhancer romoter marks at CTCF motif.
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2011
DOI: 10.1158/2159-8290.22540900.V1
Abstract: Supplementary Data from PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539128
Abstract: Loss of Arid1a or Smarcb1 promotes increased accessibility to binding motifs for non-canonical BAF complexes.
Publisher: F1000 Research Ltd
Date: 28-09-2018
DOI: 10.12688/F1000RESEARCH.16409.1
Abstract: Displaying data onto anatomical structures is a convenient technique to quickly observe tissue related information. However, drawing tissues is a complex task that requires both expertise in anatomy and the arts. While web based applications exist for displaying gene expression on anatograms, other non-genetic disciplines lack similar tools. Moreover, web based tools often lack the modularity associated with packages in programming languages, such as R. Here I present gganatogram, an R package used to plot modular species anatograms based on a combination of the graphical grammar of ggplot2 and the publicly available anatograms from the Expression Atlas. This combination allows for quick and easy, modular, and reproducible generation of anatograms. Using only one command and a data frame with tissue name, group, colour, and value, this tool enables the user to visualise specific human and mouse tissues with desired colours, grouped by a variable, or displaying a desired value, such as gene-expression, pharmacokinetics, or bacterial load across selected tissues. I hope that this tool will be useful by the wider community in biological sciences. Community members are welcome to submit additional anatograms, which can be incorporated into the package. A stable version gganatogram has been deposited to neuroconductor , and a development version can be found on github/jespermaag/gganatogram .
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540903.V1
Abstract: Supplementary Data from PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539095.V1
Abstract: Effects of MEK inhibition on chromatin accessibility and thyroid differentiated gene expression in Braf-mutant cancers with homozygous loss of Swi/Snf subunit genes.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2022
DOI: 10.1158/2159-8290.CD-21-1671
Abstract: PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context–specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. See related commentary by Guil and Esteller, p. 2020. This article is highlighted in the In This Issue feature, p. 2007
Publisher: Springer Science and Business Media LLC
Date: 23-03-2017
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2020
DOI: 10.1158/2159-8290.CD-20-0735
Abstract: Reprogramming cancer differentiation confers therapeutic benefit in various disease contexts. Oncogenic BRAF silences genes required for radioiodine responsiveness in thyroid cancer. Mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage specification genes in BRAF-mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade. This article is highlighted in the In This Issue feature, p. 995
Publisher: Springer Science and Business Media LLC
Date: 13-09-2014
DOI: 10.1007/S10571-013-9984-X
Abstract: Cannabinoid (CB) ligands have demonstrated neuroprotective properties. In this study we compared the effects of a erse set of CB ligands against β amyloid-mediated neuronal toxicity and activated microglial-conditioned media-based neurotoxicity in vitro, and compared this with a capacity to directly alter β amyloid (Aβ) fibril or aggregate formation. Neuroblastoma (SH-SY5Y) cells were exposed to Aβ1-42 directly or microglial (BV-2 cells) conditioned media activated with lipopolysaccharide (LPS) in the presence of the CB1 receptor-selective agonist ACEA, CB2 receptor-selective agonist JWH-015, phytocannabinoids Δ(9)-THC and cannabidiol (CBD), the endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide or putative GPR18/GPR55 ligands O-1602 and abnormal-cannabidiol (Abn-CBD). TNF-α and nitrite production was measured in BV-2 cells to compare activation via LPS or albumin with Aβ1-42. Aβ1-42 evoked a concentration-dependent loss of cell viability in SH-SY5Y cells but negligible TNF-α and nitrite production in BV-2 cells compared to albumin or LPS. Both albumin and LPS-activated BV-2 conditioned media significantly reduced neuronal cell viability but were directly innocuous to SH-SY5Y cells. Of those CB ligands tested, only 2-AG and CBD were directly protective against Aβ-evoked SH-SY5Y cell viability, whereas JWH-015, THC, CBD, Abn-CBD and O-1602 all protected SH-SY5Y cells from BV-2 conditioned media activated via LPS. While CB ligands variably altered the morphology of Aβ fibrils and aggregates, there was no clear correlation between effects on Aβ morphology and neuroprotective actions. These findings indicate a neuroprotective action of CB ligands via actions at microglial and neuronal cells.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539131.V1
Abstract: SWI/SNF alterations in human thyroid cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539110.V1
Abstract: Impact of Swi/Snf subunit loss on serum TSH levels and chromatin landscape.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539095
Abstract: Effects of MEK inhibition on chromatin accessibility and thyroid differentiated gene expression in Braf-mutant cancers with homozygous loss of Swi/Snf subunit genes.
Publisher: Springer Science and Business Media LLC
Date: 12-2017
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539131
Abstract: SWI/SNF alterations in human thyroid cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539098
Abstract: Effects of MEK inhibition on chromatin accessibility at thyroid lineage TF targets and at key MAPK downstream effectors in TBraf and TBraf/Swi-Snf deficient tumors.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22539107.V1
Abstract: Impact of Arid1a, Arid2 and Smarcb1 loss on thyroid lineage TF expression and chromatin accessibility.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.NEURO.2011.12.015
Abstract: Cannabinoids have been widely reported to have neuroprotective properties in vitro and in vivo. In this study we compared the effects of CB1 and CB2 receptor-selective ligands, the endocannabinoid anandamide and the phytocannabinoid cannabidiol, against oxidative stress and the toxic hallmark Alzheimer's protein, β-amyloid (Aβ) in neuronal cell lines. PC12 or SH-SY5Y cells were selectively exposed to either hydrogen peroxide, tert-butyl hydroperoxide or Aβ, alone or in the presence of the CB1 specific agonist arachidonyl-2'-chloroethylamide (ACEA), CB2 specific agonist JWH-015, anandamide or cannabidiol. Cannabidiol improved cell viability in response to tert-butyl hydroperoxide in PC12 and SH-SY5Y cells, while hydrogen peroxide-mediated toxicity was unaffected by cannabidiol pretreatment. Aβ exposure evoked a loss of cell viability in PC12 cells. Of the cannabinoids tested, only anandamide was able to inhibit Aβ-evoked neurotoxicity. ACEA had no effect on Aβ-evoked neurotoxicity, suggesting a CB1 receptor-independent effect of anandamide. JWH-015 pretreatment was also without protective influence on PC12 cells from either pro-oxidant or Aβ exposure. None of the cannabinoids directly inhibited or disrupted preformed Aβ fibrils and aggregates. In conclusion, the endocannabinoid anandamide protects neuronal cells from Aβ exposure via a pathway unrelated to CB1 or CB2 receptor activation. The protective effect of cannabidiol against oxidative stress does not confer protection against Aβ exposure, suggesting ergent pathways for neuroprotection of these two cannabinoids.
Location: United States of America
No related grants have been discovered for Jesper Maag.