Targeted sequencing of brain AVM tissues
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ABSTRACT:
PROVIDER: EGAS00001006729 | EGA |
REPOSITORIES: EGA
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Project description:Targeted sequencing data to look for the involvement of genes in the RAS-MAPK pathway, angiogenesis and brain vascular disorders among others, in brain AVMs
| EGAD00001009695 | EGA
Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>
| phs001072 | dbGaP
Project description:RAS-MAPK activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series of diangosis and relapsed ALL. To evaluate the specific role of RAS-MAPK activating mutations in chemotherapy resistance in ALL we used primary isogenic leukemia cells expressing either Kras wild type or a mutant oncogenic form of Kras (Kras G12D) Mechanistically, functional dissection of Kras wild type and mutant Kras (Kras G12D) isogenic ALL cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras-expressing ALL cells. These results pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL
2018-11-01 | GSE75090 | GEO
Project description:Background: The Ras pathway genes KRAS, BRAF or ERBBs have somatic mutations in ~60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway, or whether they have acquired mutations in genes hitherto not known to belong to the pathway. Methods: To address the second possibility, and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted. Results: Of the 163 recurrently targeted genes in the two different genetic backgrounds, one third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, 9 genes also mutated in human colorectal cancers were identified. Among these, stable knock-down of FOXO3, NCOA3, and TCF7L2 restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of GLUT1 and Ras pathway related proteins. Knock-down of NCOA3 and FOXO3 significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells. Conclusions: This work establishes a proof-of-concept that human cell based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer.
2018-02-20 | PXD008382 | Pride
Project description:Activating mutants of RAS are commonly found in many human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we have developed a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. Affinity purification were performed on PATU8902 and H358 cell lines that contain KRAS(G12V) and KRAS(G12C), respectively, but not from growth factor stimulated HEK293T cells containing only wild-type RAS. The mass spectrometric data was acquired in data dependent mode to show the clear enrichment of KRAS in the 2 cell lines that carry the mutated RAS. In addition, a targeted analysis was performed for the peptide carrying the G12V mutation as well as the wild type KRAS peptide to further verify enrichment of only the KRAS mutant.
2020-12-07 | MSV000086569 | MassIVE
Project description:We compared the transformation efficiencies of mutant NRAS and KRAS in immortal, non-transformed Ink4a/Arf-deficient melanocytes. NRAS mutation leads to increased cellular proliferation and is potently tumorigenic. In contrast, KRAS mutation does not enhance melanocyte proliferation and is only weakly tumorigenic on its own. While both NRAS and KRAS activate MAPK signaling, only NRAS enhances MYC activity in these cells. Our data suggests that the activity of specific RAS isoforms is context dependent and provides a possible explanation for the prevalence of NRAS mutations in melanoma.In addition, understanding this mechanism will have important implications for cancer therapies targeting RAS pathways. Keywords: RAS isoforms Common Reference
2010-06-10 | E-GEOD-6194 | biostudies-arrayexpress
Project description:Microarray expression data generated to compare the biological impact of KrasG12D allelic duplication in p53null mouse embryonic fibroblasts (MEFs). The RAS/MAPK-signalling pathway is frequently deregulated in non-small cell lung cancer (NSCLC), often through activating mutations in KRAS. Mouse models demonstrated that activation of a single endogenous mutant Kras allele is sufficient to promote lung tumour formation, but acquisition of other genetic alterations is required for malignant progression. Using a well-established lung cancer mouse model we recently demonstrated that advanced KrasG12D-driven spontaneous tumours frequently exhibit enhanced MAPK signalling and KrasG12D allelic enrichment (KrasG12D/Kraswild-type>1), implying that mutant Kras copy gains are positively selected during lung cancer progression. To compare the oncogenic impact of a single mutant allele versus additional mutant Kras copy gain, we carried out a comprehensive analysis of mutant Kras homozygous and heterozygous MEFs and lung cancer cells and show that these genotypes are phenotypically distinct. Title: Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities Authors: Emma M Kerr, Edoardo Gaude, Frances K Turrell, Christian Frezza and Carla P Martins
2016-02-24 | GSE75871 | GEO
Project description:Microarray expression data generated to compare the biological impact of KrasG12D allelic duplication in p53null mouse embryonic fibroblasts (MEFs). The RAS/MAPK-signalling pathway is frequently deregulated in non-small cell lung cancer (NSCLC), often through activating mutations in KRAS. Mouse models demonstrated that activation of a single endogenous mutant Kras allele is sufficient to promote lung tumour formation, but acquisition of other genetic alterations is required for malignant progression. Using a well-established lung cancer mouse model we recently demonstrated that advanced KrasG12D-driven spontaneous tumours frequently exhibit enhanced MAPK signalling and KrasG12D allelic enrichment (KrasG12D/Kraswild-type>1), implying that mutant Kras copy gains are positively selected during lung cancer progression. To compare the oncogenic impact of a single mutant allele versus additional mutant Kras copy gain, we carried out a comprehensive analysis of mutant Kras homozygous and heterozygous MEFs and lung cancer cells and show that these genotypes are phenotypically distinct. Title: Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities Authors: Emma M Kerr, Edoardo Gaude, Frances K Turrell, Christian Frezza and Carla P Martins For MEF generation, KrasLSL-G12D/+ ;p53Fx/Fx mixed background (C57Bl/6/129/Sv) animals were interbred and embryos collected at day E12.5 to overcome KrasLSL-G12D/G12D embryonic lethality and Cre-mediated recombination performed immediately after MEF generation. Cells were cultured in DMEM supplemented with 10% FBS, 2 mM L-Glutamine for one passage and then infected with adenovirus-Cre (5âÃâ107âplaque-forming units/1 x 106 cells). Recombination of LoxP sites was confirmed by PCR analysis. Three independent embryos per genotype were analysed using GPL6887 Illumina MouseWG-6 v2.0 expression beadchip.
2016-02-24 | E-GEOD-75871 | biostudies-arrayexpress
Project description:The KRAS G12D mutation is a key oncogenic driver in many solid tumors, including pancreatic, gastric, and colorectal cancers. While recent preclinical studies have characterized features associated with innate and acquired KRAS G12D inhibitor resistance, strategies to overcome resistance, especially in the gastrointestinal cancer context, remain underexplored. Here, we generated nine gastrointestinal cancer models of acquired resistance to the KRAS G12D-selective inhibitor MRTX1133. We identified the enrichment of angiogenesis, hypoxia, and epithelial-to-mesenchymal transition (EMT) in an isogenic patient-derived organoid model of acquired resistance by single-cell RNA sequencing. In the nine resistant models, VEGFA expression and VEGFR2 phosphorylation were unanimously increased. Subsequent mechanistic studies revealed that an autocrine VEGFA signaling loop, initiated by an increased interaction between KRAS and PI3Kγ, drives both EMT and RAS independence. Elevated mitochondrial oxidative stress in resistant cells led to CCT2-mediated KRAS stabilization, thereby enhancing PI3Kγ activity. Moreover, we observed that cancer-vascular paracrine signaling both amplified angiogenesis and EMT signatures in cancer cells and promoted endothelial cell proliferation. Significantly, disruption of VEGFA signaling reversed EMT induction and restored sensitivity to MRTX1133. Concordantly, in mouse xenograft models, the combination of anti-VEGFR2 therapy and MRTX1133 rechallenge significantly reduced tumor growth, angiogenesis, and proliferation markers without adverse effects on body weight. These findings identify a critical role for VEGFA signaling in resistance to KRAS G12D inhibition and provide a rationale for combination therapies targeting angiogenesis in gastrointestinal cancers.
2025-03-03 | GSE290526 | GEO
Project description:The KRAS G12D mutation is a key oncogenic driver in many solid tumors, including pancreatic, gastric, and colorectal cancers. While recent preclinical studies have characterized features associated with innate and acquired KRAS G12D inhibitor resistance, strategies to overcome resistance, especially in the gastrointestinal cancer context, remain underexplored. Here, we generated nine gastrointestinal cancer models of acquired resistance to the KRAS G12D-selective inhibitor MRTX1133. We identified the enrichment of angiogenesis, hypoxia, and epithelial-to-mesenchymal transition (EMT) in an isogenic patient-derived organoid model of acquired resistance by single-cell RNA sequencing. In the nine resistant models, VEGFA expression and VEGFR2 phosphorylation were unanimously increased. Subsequent mechanistic studies revealed that an autocrine VEGFA signaling loop, initiated by an increased interaction between KRAS and PI3Kγ, drives both EMT and RAS independence. Elevated mitochondrial oxidative stress in resistant cells led to CCT2-mediated KRAS stabilization, thereby enhancing PI3Kγ activity. Moreover, we observed that cancer-vascular paracrine signaling both amplified angiogenesis and EMT signatures in cancer cells and promoted endothelial cell proliferation. Significantly, disruption of VEGFA signaling reversed EMT induction and restored sensitivity to MRTX1133. Concordantly, in mouse xenograft models, the combination of anti-VEGFR2 therapy and MRTX1133 rechallenge significantly reduced tumor growth, angiogenesis, and proliferation markers without adverse effects on body weight. These findings identify a critical role for VEGFA signaling in resistance to KRAS G12D inhibition and provide a rationale for combination therapies targeting angiogenesis in gastrointestinal cancers.
2025-03-02 | GSE290487 | GEO