Similar Datasets
Project description:Transcription factors (TFs) are important mediators of aberrant transcriptional programs in cancer cells. In this study, we focused on TF activity (TFa) as a new biomarker for cell line-selective anti-proliferative effects, in that high TFa predicts sensitivity to loss-of-function of a given gene (i.e., genetic dependencies (GD)). Our linear regression-based framework identified 3,043 pan-cancer and 3,952 cancer-type-specific candidate TFa-GD associations from cell line data, which were then cross-examined for impact on survival in patient data. One of the most prominent biomarkers was TEAD1 activity, whose associations with its predicted GDs were validated through experimental evidence as proof of concept. Overall, these TFa-GD pairs represent an attractive resource for identifying innovative, biomarker-driven hypotheses for drug discovery programs in oncology.
2024-04-29 | GSE254799 | GEO
Project description:Transcription factors (TFs) are important mediators of aberrant transcriptional programs in cancer cells. In this study, we focused on TF activity (TFa) as a new biomarker for cell line-selective anti-proliferative effects, in that high TFa predicts sensitivity to loss-of-function of a given gene (i.e., genetic dependencies (GD)). Our linear regression-based framework identified 3,047 pan-cancer and 3,952 cancer-typespecific candidate TFa-GD associations from cell line data, which were then crossexamined for impact on survival in patient cohorts. One of the most prominent biomarkers was TEAD1 activity, whose associations with its predicted GDs were validated through experimental evidence as proof of concept. Overall, these TFa-GD associations represent an attractive resource for identifying innovative, biomarkerdriven hypotheses for drug discovery programs in oncology.
2024-04-29 | GSE263747 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-12-23 | E-GEOD-50625 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-12-31 | GSE169725 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-04-01 | GSE74529 | GEO
Project description:A comprehensive understanding of the molecular vulnerabilities of every type of cancer will provide a powerful roadmap to guide therapeutic approaches. Efforts such as The Cancer Genome Atlas Project will identify genes with aberrant copy number, sequence, or expression in various cancer types, providing a survey of the genes that may have a causal role in cancer. A complementary approach is to perform systematic loss-of-function studies to identify essential genes in particular cancer cell types. We have begun a systematic effort, termed Project Achilles, aimed at identifying genetic vulnerabilities across large numbers of cancer cell lines. Here, we report the assessment of the essentiality of 11,194 genes in 102 human cancer cell lines. We show that the integration of these functional data with information derived from surveying cancer genomes pinpoints known and previously undescribed lineage-specific dependencies across a wide spectrum of cancers. In particular, we found 54 genes that are specifically essential for the proliferation and viability of ovarian cancer cells and also amplified in primary tumors or differentially overexpressed in ovarian cancer cell lines. One such gene, PAX8, is focally amplified in 16% of high-grade serous ovarian cancers and expressed at higher levels in ovarian tumors. Suppression of PAX8 selectively induces apoptotic cell death of ovarian cancer cells. These results identify PAX8 as an ovarian lineage-specific dependency. More generally, these observations demonstrate that the integration of genome-scale functional and structural studies provides an efficient path to identify dependencies of specific cancer types on particular genes and pathways.
| S-EPMC3145679 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2010-02-18 | GSE19636 | GEO
Project description:PURPOSE:Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110? signaling for survival. EXPERIMENTAL DESIGN:Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treated with pan-class I PI3K, p110?, and p110? isoform-specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells. RESULTS:EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110? inhibitors GSK2636771 and AZD6482, and only in combination with the p110? selective inhibitor A66 was a decrease in cell viability observed. CONCLUSIONS:Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110? alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required.
| S-EPMC3700760 | biostudies-literature
Project description:BackgroundTransposable elements (TE) are commonly regarded as "junk DNA" with no apparent regulatory roles in the human genome. However, a growing body of evidence demonstrates that some TEs exhibit regulatory activities in a range of biological pathways and diseases, with notable examples in bile metabolism and innate immunity. TEs are typically suppressed by epigenetic modifications in healthy somatic tissues, which prevents both undesirable effects of insertional mutagenesis, and also unwanted gene activation. Interestingly, TEs are widely reported to be dysregulated in epithelial cancers, and while much attention has been paid to their effects on genome instability, relatively little has been reported on their effects on gene regulation. Here, we investigated the contribution of TEs to the transcriptional regulation in breast cancer cell lines.ResultsWe found that a subset of TE subfamilies were enriched in oncogenic transcription factor binding sites and also harboured histone marks associated with active transcription, raising the possibility of these subfamilies playing a broad role in breast cancer transcriptional regulation. To directly assess promoter activity in triple negative breast cancer cell lines, we identified four breast cancer-associated genes with putative TE-derived promoters. TE deletion confirmed a contribution to promoter activity in all cases, and for two examples the promoter activity was almost completely contained within the TE.ConclusionsOur findings demonstrate that TEs provide abundant oncogenic transcription factor binding sites in breast cancer and that individual TEs contain substantial promoter activity. Our findings provide further evidence for transcriptional regulation of human genes through TE exaptation by demonstrating the regulatory potential of TEs in multiple breast cancer cell lines.
| S-EPMC6486989 | biostudies-literature
Project description:BACKGROUND: It is known that transcription factors frequently act together to regulate gene expression in eukaryotes. In this paper we describe a computational analysis of transcription factor site dependencies in human, mouse and rat genomes. RESULTS: Our approach for quantifying tendencies of transcription factor binding sites to co-occur is based on a binding site scoring function which incorporates dependencies between positions, the use of information about the structural class of each transcription factor (major/minor groove binder), and also considered the possible implications of varying GC content of the sequences. Significant tendencies (dependencies) have been detected by non-parametric statistical methodology (permutation tests). Evaluation of obtained results has been performed in several ways: reports from literature (many of the significant dependencies between transcription factors have previously been confirmed experimentally); dependencies between transcription factors are not biased due to similarities in their DNA-binding sites; the number of dependent transcription factors that belong to the same functional and structural class is significantly higher than would be expected by chance; supporting evidence from GO clustering of targeting genes. Based on dependencies between two transcription factor binding sites (second-order dependencies), it is possible to construct higher-order dependencies (networks). Moreover results about transcription factor binding sites dependencies can be used for prediction of groups of dependent transcription factors on a given promoter sequence. Our results, as well as a scanning tool for predicting groups of dependent transcription factors binding sites are available on the Internet. CONCLUSION: We show that the computational analysis of transcription factor site dependencies is a valuable complement to experimental approaches for discovering transcription regulatory interactions and networks. Scanning promoter sequences with dependent groups of transcription factor binding sites improve the quality of transcription factor predictions.
| S-EPMC2770556 | biostudies-literature