Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA271792 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Genetic suppression of EGFR* induction led to significant tumor regression and prolonged survival. But in spite of the initial response, the tumors relapsed invariably and propagated independent of EGFR*. We used microarrys to directly compare geen expression of control and relapse tumors and identified gene sets specifically activated in relapse tumors. Control and relasped glioma samples upon mutant EGFR extinction were selected for RNA extraction and hybridization on Affymetrix microarrays.
2015-01-08 | E-GEOD-64751 | biostudies-arrayexpress
Project description:To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Genetic suppression of EGFR* induction led to significant tumor regression and prolonged survival. But in spite of the initial response, the tumors relapsed invariably and propagated independent of EGFR*. We used microarrys to directly compare geen expression of control and relapse tumors and identified gene sets specifically activated in relapse tumors.
2015-01-08 | GSE64751 | GEO
Project description:Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histological progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution towards an IDHwt-like phenotype.
2023-12-13 | GSE248471 | GEO
Project description:Metastatic relapse from treatment failure has been a formidable challenge to finding a cure for EGFR-mutant lung cancer. Metastasis to the brain is a severe complication for 45% of patients with EGFR-mutant lung cancer that drastically reduces their quality of life and survival. Here, we demonstrate that genetic inhibition of S100A9, ALDH1A1, RAR, or pharmacological inhibition of the RA pathway using pan-RAR inhibitors significantly reduces brain relapse from osimertinib-refractory cancer cells. Our study has therefore revealed a novel S100A9-ALDH1A1-RA signaling axis in the EGFR-mutant lung cancer cells that drives osimertinib-refractory metastatic brain relapse and identified a potential vulnerability in lung cancer cells that can be therapeutically targeted to prolong progression-free survival in EGFR-mutant lung cancer patients.
2023-12-20 | GSE190704 | GEO
Project description:Cancer genome sequencing has uncovered substantial complexity in the mutational landscape of tumors. Given this complexity, experimental approaches are necessary to establish the impact of combinations of genetic alterations on tumor biology and to uncover genotype-dependent effects on drug sensitivity. In lung adenocarcinoma, EGFR mutations co-occur with many putative tumor suppressor gene alterations, however the extent to which these alterations contribute to tumor growth and their response to therapy in vivo has not been explored experimentally. By integrating a novel mouse model of oncogenic EGFR-driven Trp53-deficient lung adenocarcinoma with multiplexed CRISPR–Cas9-mediated genome editing and tumor barcode sequencing, we quantified the effects of inactivation of ten putative tumor suppressor genes. Inactivation of Apc, Rb1, or Rbm10 most strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 – which were the strongest drivers of tumor growth in an oncogenic Kras-driven model – reduced EGFR-driven tumors growth. These results were consistent with the relative frequency of these tumor suppressor gene alterations in human EGFR and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduced the sensitivity of tumors to osimertinib in the EGFRL858R;p53flox/flox model. Importantly, in human EGFR/TP53 mutant lung adenocarcinomas, mutations in the KEAP1 pathway correlated with decreased time on tyrosine kinase inhibitor treatment. Our study highlights how genetic alterations can have dramatically different biological consequences depending on the oncogenic context and that the fitness landscape can shift upon drug treatment.
2021-02-01 | GSE146550 | GEO
Project description:Oncogene-driven lung cancers such as those with activating mutations in the epidermal growth factor receptor (EGFR) often harbor additional co-occurring genetic alterations. The significance of most alterations co-occurring with mutant EGFR remains unclear. We report the impact of loss of the mRNA splicing factor RBM10 in human EGFR mutant lung cancer. RBM10 loss decreased EGFR inhibitor efficacy in patient-derived EGFR mutant tumor models. RBM10 regulated mRNA splicing of the mitochondrial apoptotic regulator Bcl-x. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by altering Bcl-x splicing, decreasing Bcl-xS (pro-apoptotic) and increasing Bcl-xL (anti-apoptotic) levels. Co-inhibition of Bcl-xL and mutant EGFR overcomes resistance induced by RBM10 loss. RBM10 loss was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Inactivation of the splicing factor RBM10 is a key co-occurring genetic alteration in EGFR mutant tumors that limits EGFR inhibitor efficacy and a potential biomarker of Bcl-xL inhibitor response.
2022-06-04 | GSE199240 | GEO
Project description:Non-small cell lung cancers (NSCLCs) harboring activating EGFR mutants show dramatic responses to EGFR TKIs, such as erlotinib and geffitinib. However, nearly all patients show relapse within 1 year after initial treatment. We used microarrays to detail global gene expression changes in EGFR mutant cells vs. WT cells responding to erlotinib. 4 EGFR mutant and 4 WT NSCLC cells were treated with or without erlotinib for 24 hr, followed by RNA extraction and hybridization on Affymetrix microarrays.
2014-05-16 | E-GEOD-57156 | biostudies-arrayexpress
Project description:Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC. Examination of mRNA levels in DMSO and gefitinib-resistant cultures of HCC4006 and HCC827. Each group has two replicates.
2016-03-29 | E-GEOD-79688 | biostudies-arrayexpress
Project description:Analysis of mouse glioma tumors (in RAG1-/- mouse host) overexpressing Control(C) or Slug(S) viruses, and treated with doxycyclin(D) to turn off EGFRviii expression. Results provide insight into molecular basis of EGFRviii targeted therapy-induced resistence in GBM. By utilizing animals engineered with doxycycline (dox)-off oncogenic EGFRvIII transgene and conditional Ink4a/Arf and Pten alleles (Nestin-CreERT2; Ink4aL/L; PtenL/L; hGFAP_tTA; tetO-EGFRvIII, designated iEIP), we previously demonstrated that sustained oncogenic EGFR signaling was required for maintenance of EGFR-driven glioma progression and suppression of oncogenic EGFRvIII transgene expression induces tumor regression. But despite of a robust initial response, the regressed tumors relapsed inevitably. The finding that relapsed tumors had escaped oncogenic EGFR signaling addiction promoted our search for potential genetic events that might fuel the resistance development. Three relapse and two matched treatment-naïve tumors derived from the same parental line were analyzed by whole exome sequencing.
2019-01-01 | GSE108658 | GEO
Project description:EGFR inhibitors (EGFRi) are effective against EGFR mutant lung cancers. The efficacy of these drugs however is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, T790M. We recently demonstrated that T790M can arise de novo during treatment (Hata et al., Nature Medicine 2016); it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells (referred to as drug tolerant cells (DTCs)) prior to acquiring secondary mutations like T790M. We have developed DTCs to EGFRi in EGFR mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink EGFR mutant lung cancer tumors in vivo.
2018-07-25 | GSE117610 | GEO