Rational targeting of dynamic tumor subclones in relapsing human glioblastoma
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PROVIDER: PRJNA606087 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastoma therapy relies on the alkylating drug temozolomide (TMZ) administered to irradiated patients post-neurosurgery, which increases overall survival but cannot prevent fatal disease relapse. Using clinical samples and glioblastoma models, we here identify TMZ-driven enrichment of ALDH1A1+ tumor subclones acquiring AKT-dependent drug resistance en route to relapse. We demonstrate that this recurrent phenotype switch is predictable and can be countered by a sequential rather than simultaneous combinatorial treatment approach.
2020-02-12 | GSE145128 | GEO
Project description:Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design: Here, we used 33 single cell–derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma
2016-12-19 | GSE72732 | GEO
Project description:Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design: Here, we used 33 single cell–derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma
2016-12-19 | GSE72927 | GEO
Project description:In order to identify factors involved in TMZ-resistance, we engineered different TMZ-resistant glioblastoma cell lines. Wildtype cells were treated twice a week in duplicate with a clinically relevant concentration of TMZ (33 µM) for multiple weeks, until two individual resistant subclones were generated. Gene expression profiling was performed to identify differentially expressed genes in the resistant cells compared to their wildtype cells. three wildtype glioblastoma cell lines (U87, LNZ308, Hs683) and their resistant subclones, two of each wildtype, were analyzed The experiments were performed technically as dual channel but processed/normalized as single channel (i.e. two sample records per one raw data file). The raw data file for each sample is indicated in the sample description field but linked as Series supplementary file.
2014-01-01 | E-GEOD-53014 | biostudies-arrayexpress
Project description:In order to identify factors involved in TMZ-resistance, we engineered different TMZ-resistant glioblastoma cell lines. Wildtype cells were treated twice a week in duplicate with a clinically relevant concentration of TMZ (33 µM) for multiple weeks, until two individual resistant subclones were generated. Gene expression profiling was performed to identify differentially expressed genes in the resistant cells compared to their wildtype cells.
2014-01-01 | GSE53014 | GEO
Project description:U87MG is a glioblastoma cell line that shows substantial heterogeneity despite long-term passaging. We used microarrays to identify variations in gene expression that are associated with phenotypic differences among subclones derived from U87MG.
2015-02-12 | GSE54967 | GEO
Project description:One aspect of intra-tumoral heterogeneity in glioblastoma involves subpopulations of cells capable of self-renewal and indefinite propagation. Conceptually, this capacity is frequently treated as a static property. Here we provide data suggesting that tumorigenicity in glioblastomais a dynamic property that can be acquired or lost. Integrated expression analyses suggest that tumorigenicity is determined by the level of MYC expression relative to a threshold. Transitions between tumorigenic and non-tumorigenic cell states are associated with changes in histone modifications at the MYC locus, suggesting tumorigenicity is epigenetically regulated. To verify genomic stability at the nucleotide level, we tested whether subclones derived from single cells shared common Single-Nucleotide Polymorphisms (SNPs). Ten single cell-derived subclones of U87MG underwent SNP profiling by Affymetrix Human Mapping 250K Nsp arrays.
2014-03-28 | E-GEOD-56316 | biostudies-arrayexpress
Project description:Genetic heterogeneity though common in tumors has been rarely documented in cell lines. To examine how often B-lymphoma cell lines are comprised of subclones, we performed immunoglobulin (Ig) heavy chain hypermutation analysis. Revealing that subclones are not rare in B-cell lymphoma cell lines, 6/49 Ig hypermutated cell lines (12%) consisted of subclones with individual Ig mutations. Subclones were also identified in 2/284 leukemia/lymphoma cell lines exhibiting bimodal CD marker expression. We successfully isolated 10 subclones from four cell lines HG3, SU-DHL-5, TMD-8, U-2932). Whole exome sequencing was performed to molecularly characterize these subclones. We in detail describe the clonal structure of cell line HG3, derived from chronic lymphocytic leukemia. HG3 consists of three lineages each bearing clone-specific aberrations, gene expression and DNA methylation patterns. While donor patient leukemic cells were CD5+ , two of three HG3 subclones had independently lost this marker. CD5 on HG3 cells was regulated by epigenetic/transcriptional mechanisms rather than by alternative splicing as reported hitherto. In conclusion, we show that the presence of subclones in cell lines carrying individual mutations and characterized by sets of differentially expressed genes is not uncommon. We show also that these subclones can be useful isogenic models for regulatory and functional studies.
2016-09-30 | E-MTAB-4955 | biostudies-arrayexpress
Project description:Medium conditioned by LLC cells stimulates thermogenic gene expression when added onto primary adipocytes. We generated single cell colonies from parental LLC cells. Media conditioned by the subclones stimulated thermogenic gene expression in primary adipocytes at varying degrees. Subclones 2, 3, 6 and 28 produce significantly larger amount of thermogenic activity than the subclones 18, 19, 23 and 24. We compared gene expression profiles of these subclones to identify secreted factors enriched in the more thermogenic clones.
2014-07-13 | GSE57797 | GEO
Project description:Mutational dynamics between primary and relapsing neuroblastoma
| PRJEB9535 | ENA