A5089614989- Gene Regulatory Network Analysis
- Bioinformatics and Genomic Networks
- Single-cell and spatial transcriptomics
- Computational Drug Discovery Methods
- Cell Image Analysis Techniques
- Receptor Mechanisms and Signaling
- Melanoma and MAPK Pathways
- Advanced Biosensing Techniques and Applications
- Molecular Biology Techniques and Applications
- Advanced Fluorescence Microscopy Techniques
- Advanced Proteomics Techniques and Applications
- Cancer Genomics and Diagnostics
- Gene expression and cancer classification
- Mathematical Biology Tumor Growth
- Advanced biosensing and bioanalysis techniques
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Protein Kinase Regulation and GTPase Signaling
- Histone Deacetylase Inhibitors Research
- Cancer-related Molecular Pathways
- Cellular Mechanics and Interactions
- Monoclonal and Polyclonal Antibodies Research
- RNA Research and Splicing
- RNA modifications and cancer
- PI3K/AKT/mTOR signaling in cancer
Icahn School of Medicine at Mount Sinai
2015-2025
Clemson University
2017-2025
University of Calgary
2023
Bristol-Myers Squibb (United States)
2023
Universidade Federal do Rio de Janeiro
2023
Cancer Research UK Scotland Institute
2009-2022
Texas Tech University
2015
Pfizer (United States)
2015
Columbia University
2015
Dana-Farber Cancer Institute
2015
First identified in the early 1980s as retroviral oncogenes, Raf proteins have been objects of intense research. The discoveries 10 years later that family members (Raf-1, B-Raf, and A-Raf) are bona fide Ras effectors upstream activators ubiquitous ERK pathway increased interest these primarily because central role this cascade plays cancer development. important was corroborated 2002 with discovery B-Raf genetic mutations a large number tumors. This led to intensified drug development...
Western blot data are widely used in quantitative applications such as statistical testing and mathematical modelling. To ensure accurate quantitation comparability between experiments, replicates must be normalised, but it is unclear how the available methods affect properties of data. Here we evaluate three commonly normalisation strategies: (i) by fixed point or control; (ii) sum all points a replicate; (iii) optimal alignment replicates. We consider these different strategies coefficient...
Dynamic interactions between RhoA and Rac1, members of the Rho small GTPase family, play a vital role in control cell migration. Using predictive mathematical modeling, mass spectrometry-based quantitation network components, experimental validation MDA-MB-231 mesenchymal breast cancer cells, we show that containing RhoA, PAK family kinases can produce bistable, switch-like responses to graded inhibition. chemical inhibitor PAK, demonstrate cellular Rac1 activation levels respond...
Analysis of ERK pathway circuitry suggests appropriate targets for inhibition, providing a guide drug development.
Article13 November 2007Open Access Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses Marc R Birtwistle Department Chemical Engineering, University Delaware, Newark, DE, USA Pathology, Anatomy, Cell Biology, Thomas Jefferson University, Philadelphia, PA, Search for more papers by this author Mariko Hatakeyama Computational Experimental Systems Biology Group, RIKEN Genomic Sciences Center, Yokohama, Kanagawa, Japan Noriko Yumoto Babatunde A Ogunnaike...
Highlights•Implementing FAIR data standards requires identification of experimental confounders•Five labs performed the same experiment on mammalian cells and compared results•Several factors affecting reproducibility were explored•Biological context had an unexpected impact robustness cell-based assaysSummaryEvidence that some high-impact biomedical results cannot be repeated has stimulated interest in practices generate findable, accessible, interoperable, reusable (FAIR) data. Multiple...
Abstract Background Glioblastoma (GBM) remains a largely incurable disease as current therapy fails to target the invasive nature of glioma growth in progression and recurrence. Here, we use FDA-approved drug small molecule Hippo inhibitor Verteporfin (VP) YAP-TEAD activity, known mediate convergent aspects tumor invasion/metastasis, assess drug’s efficacy survival benefit GBM models. Methods Up 8 low-passage patient-derived cell lines with distinct genomic drivers, including 3...
Background BRAFV600 inhibitors have offered a new gateway for better treatment of metastatic melanoma. However, the overall efficacy has been lower than expected in clinical trials, and many patients shown resistance to drug's effect. We hypothesized that somatic mutations Phosphoinositide 3-Kinase (PI3K) pathway, which promotes proliferation survival, may coincide with contribute chemotherapeutic resistance. Methods performed mutation profiling study using 454 FLX pyrosequencing platform...
Cell-to-cell variability in protein expression can be large, and its propagation through signaling networks affects biological outcomes. Here, we apply deterministic probabilistic models biochemical measurements to study how network topologies cell-to-cell abundance variations interact shape responses.We observe bimodal distributions of extracellular signal-regulated kinase (ERK) responses epidermal growth factor (EGF) stimulation, which are generally thought indicate bistable or...
Creating a cDNA library for deep mRNA sequencing (mRNAseq) is generally done by random priming, creating multiple fragments along each transcript. A 3'-end-focused approach cannot detect differential splicing, but has potentially higher throughput at lower cost, with the ability to improve quantification using transcript molecule counting unique molecular identifiers (UMI) that correct PCR bias. Here, we compare an implementation of such 3'-digital gene expression (3'-DGE) "conventional"...
Abstract Mass cytometry offers the advantage of allowing simultaneous measurement a greater number parameters than conventional flow cytometry. However, to date, mass has lacked reliable alternative light scatter properties that are commonly used as cell size metric in (forward intensity—FSC). Here, we report development two plasma membrane staining assays evaluate mammalian experiments. One is based on wheat germ agglutinin (WGA) and other Osmium tetroxide (OsO 4 ) staining, both which have...
Upregulation of the extracellular signal-regulated kinase (ERK) pathway has been shown to contribute tumour invasion and progression. Since two predominant ERK isoforms (ERK1 ERK2) are highly homologous have indistinguishable activities in vitro, both enzymes were believed be redundant interchangeable. To challenge this view, here we show that ERK2 silencing inhibits invasive migration MDA-MB-231 cells, re-expression but not ERK1 restores normal phenotype. A detailed quantitative analysis...
Most cancer cells harbor multiple drivers whose epistasis and interactions with expression context clouds drug combination sensitivity prediction. We constructed a mechanistic computational model that is context-tailored by omics data to capture regulation of stochastic proliferation death pan-cancer driver pathways. Simulations experiments explore how the coordinated dynamics RAF/MEK/ERK PI-3K/AKT kinase activities in response synergistic mitogen or combinations control cell fate specific...
Individual cells in clonal populations often respond differently to environmental changes; for binary phenotypes, such as cell death, this can be measured a fractional response. These types of responses have been attributed cell-intrinsic stochastic processes and variable abundances biochemical constituents, proteins, but the influence organelles is still under investigation. We use response TNF-related apoptosis inducing ligand (TRAIL) new statistical framework determining parameter on...
Abstract The phenotype of a cell and its underlying molecular state is strongly influenced by extracellular signals, including growth factors, hormones, matrix proteins. While these signals are normally tightly controlled, their dysregulation leads to phenotypic states associated with diverse diseases. To develop detailed understanding the linkage between changes, we generated comprehensive dataset that catalogs transcriptional, proteomic, epigenomic responses MCF10A mammary epithelial cells...
Abstract Understanding the dynamics of intracellular signaling pathways, such as ERK1/2 (ERK) and Akt1/2 (Akt), in context cell fate decisions is important for advancing our knowledge cellular processes diseases, particularly cancer. While previous studies have established associations between ERK Akt activities proliferative fate, heterogeneity single-cell responses adds complexity to this understanding. This study employed a data-driven approach address challenge, developing machine...
Glioblastoma Multiforme (GBM) remains a particularly difficult cancer to treat, and survival outcomes remain poor. In addition the lack of dedicated drug discovery programs for GBM, extensive intratumor heterogeneity epigenetic plasticity related cell-state transitions are major roadblocks successful therapy in GBM. To study these phenomenon, publicly available snRNAseq bulk RNAseq data from patient samples were used categorize cells patients into four cell states (i.e., phenotypes), namely:...