A5065746791- CRISPR and Genetic Engineering
- Bioinformatics and Genomic Networks
- Gene expression and cancer classification
- Cancer Genomics and Diagnostics
- Gene Regulatory Network Analysis
- Microbial Metabolic Engineering and Bioproduction
- Epigenetics and DNA Methylation
- AI in cancer detection
- Advanced biosensing and bioanalysis techniques
- Evolution and Genetic Dynamics
- Single-cell and spatial transcriptomics
- RNA and protein synthesis mechanisms
- Advanced Proteomics Techniques and Applications
- Computational Drug Discovery Methods
- Hippo pathway signaling and YAP/TAZ
- Cancer, Hypoxia, and Metabolism
- Metabolomics and Mass Spectrometry Studies
- Ferroptosis and cancer prognosis
- Viral Infectious Diseases and Gene Expression in Insects
- Genomic variations and chromosomal abnormalities
- CAR-T cell therapy research
- Genetics, Bioinformatics, and Biomedical Research
- Cancer Cells and Metastasis
- Histone Deacetylase Inhibitors Research
- Fungal and yeast genetics research
University of Lisbon
2021-2025
Instituto de Engenharia de Sistemas e Computadores Investigação e Desenvolvimento
2022-2025
European Bioinformatics Institute
2012-2024
Wellcome Sanger Institute
2012-2023
Polytechnic Institute of Cávado and Ave
2020
Wellcome Trust
2013-2016
University of Minho
2011-2012
European Molecular Biology Laboratory
2012
Institut Gustave Roussy
1994-1995
Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature cancer. Using this information to guide development and application therapies in clinic is challenging. Here, we report how cancer-driven alterations identified 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, gene expression) can be mapped onto 1,001 molecularly annotated human cell lines correlated with sensitivity 265 drugs. We find...
Abstract CRISPR-Cas9 viability screens are increasingly performed at a genome-wide scale across large panels of cell lines to identify new therapeutic targets for precision cancer therapy. Integrating the datasets resulting from these studies is necessary adequately represent heterogeneity human cancers and assemble comprehensive map genetic vulnerabilities. Here, we integrated two largest public independent date (at Broad Sanger institutes) by assessing, comparing, selecting methods...
Abstract Genome-scale CRISPR-Cas9 viability screens performed in cancer cell lines provide a systematic approach to identify dependencies and new therapeutic targets. As multiple large-scale become available, formal assessment of the reproducibility these experiments becomes necessary. We analyze data from recently published pan-cancer at Broad Sanger Institutes. Despite significant differences experimental protocols reagents, we find that screen results are highly concordant across metrics...
Abstract Background Cells process signals using complex and dynamic networks. Studying how this is performed in a context cell type specific way essential to understand signaling both physiological diseased situations. Context-specific medium/high throughput proteomic data measured upon perturbation now relatively easy obtain but formalisms that can take advantage of these features build models are still comparatively scarce. Results Here we present CellNOptR , an open-source R software...
The proteome provides unique insights into disease biology beyond the genome and transcriptome. A lack of large proteomic datasets has restricted identification new cancer biomarkers. Here, proteomes 949 cell lines across 28 tissue types are analyzed by mass spectrometry. Deploying a workflow to quantify 8,498 proteins, these data capture evidence cell-type post-transcriptional modifications. Integrating multi-omics, drug response, CRISPR-Cas9 gene essentiality screens with deep...
Interferon-γ (IFN-γ) signaling mediates host responses to infection, inflammation and anti-tumor immunity. Mutations in the IFN-γ pathway cause immunological disorders, hematological malignancies, resistance immune checkpoint blockade (ICB) cancer; however, function of most clinically observed variants remains unknown. Here, we systematically investigate genetic determinants response colorectal cancer cells using CRISPR-Cas9 screens base editing mutagenesis. Deep mutagenesis JAK1 with...
Genetic screens in cancer cell lines inform gene function and drug discovery. More comprehensive screen datasets with multi-omics data are needed to enhance opportunities functionally map genetic vulnerabilities. Here, we construct a second-generation of dependencies by annotating 930 multi-omic analyze relationships between molecular markers derived from CRISPR-Cas9 screens. We identify dependency-associated expression beyond driver genes, observe many addiction driven gain rather than...
Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, well-suited for studies large While numerous groups have developed specific computational tools provide original methods analyse qualitative models, a standard format exchange models has been missing. We present Systems Biology Markup Language (SBML)...
Abstract Many gene fusions are reported in tumours and for most their role remains unknown. As used diagnostic prognostic purposes, targets treatment, it is crucial to assess function cancer. To systematically investigate the of tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer lines functionally link 8354 fusion events with genomic data, sensitivity >350 anti-cancer drugs CRISPR-Cas9 loss-of-fitness effects. Established clinically-relevant were identified....
Genome editing by CRISPR-Cas9 technology allows large-scale screening of gene essentiality in cancer. A confounding factor when interpreting screens is the high false-positive rate detecting essential genes within copy number amplified regions genome. We have developed computational tool CRISPRcleanR which capable identifying and correcting gene-independent responses to targeting. uses an unsupervised approach based on segmentation single-guide RNA fold change values across genome, without...
Abstract Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours despite having highly rearranged genomes. In this study we CRISPR screen 1191 gene pairs, including paralogues known predicted synthetic lethal interactions identify 105 combinations whose co-disruption results cellular fitness. 27 pairs influence fitness across multiple cell lines FAM50A/FAM50B , two unknown function....
CRISPR genetic screens in cancer cell models are a powerful tool to elucidate oncogenic mechanisms and identify promising therapeutic targets. The Project Score database (https://score.depmap.sanger.ac.uk/) uses genome-wide CRISPR-Cas9 dropout screening data hundreds of highly annotated genes required for fitness prioritize novel oncology currently allows users investigate the effect 18 009 tested across 323 models. Through interactive interfaces, can by selecting specific gene, model or...
Abstract CRISPR guide RNA libraries have been iteratively improved to provide increasingly efficient reagents, although their large size is a barrier for many applications. We design an optimised minimal genome-wide human CRISPR-Cas9 library (MinLibCas9) by mining existing large-scale gene loss-of-function datasets, resulting in greater than 42% reduction compared other while preserving assay sensitivity and specificity. MinLibCas9 provides backward compatibility with increases the dynamic...
Phosphoproteomic experiments are increasingly used to study the changes in signaling occurring across different conditions. It has been proposed that phosphorylation of kinase target sites can be infer when a activity is under regulation. However, these approaches have not yet benchmarked due lack appropriate benchmarking strategies.We curated phosphoproteomic and gold standard dataset containing total 184 kinase-condition pairs where regulation expected occur benchmark compare inference...
Abstract Summary: Drug versus Disease (DvD) provides a pipeline, available through R or Cytoscape, for the comparison of drug and disease gene expression profiles from public microarray repositories. Negatively correlated can be used to generate hypotheses drug-repurposing, whereas positively may infer side effects drugs. DvD allows users compare signatures with dynamic access databases Array Express, Gene Expression Omnibus data Connectivity Map. Availability implementation: package...
CRISPR-Cas9 genome editing is widely used to study gene function, from basic biology biomedical research. Structural rearrangements are a ubiquitous feature of cancer cells and their impact on the functional consequences gene-editing has not yet been assessed. Utilizing knockout screens for 250 cell lines, we demonstrate that targeting structurally rearranged regions, in particular tandem or interspersed amplifications, highly detrimental cellular fitness gene-independent manner. In...
New therapeutic targets for oral squamous cell carcinoma (OSCC) are urgently needed. We conducted genome-wide CRISPR-Cas9 screens in 21 OSCC lines, primarily derived from Asians, to identify genetic vulnerabilities that can be explored as targets. known and novel fitness genes demonstrate many previously identified OSCC-related cancer non-essential could have limited value, while other warrant further investigation their potential validate a distinctive dependency on YAP1 WWTR1 of the Hippo...
Organoid cell culture methodologies are enabling the generation of models from healthy and diseased tissue. Patient-derived cancer organoids that recapitulate genetic histopathological diversity patient tumours being systematically generated, providing an opportunity to investigate new biology therapeutic approaches. The use organoid cultures for many applications, including chemical perturbation screens, is limited due technical demands cost associated with their handling propagation. Here...