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Phenotypic plasticity is associated with non-genetic drug tolerance in several cancers. Such plasticity can arise from chromatin remodeling, transcriptomic reprogramming, and/or protein signaling rewiring, and is characterized as a cell state transition in response to molecular or physical perturbations. This, in turn, can confound interpretations of drug responses and resistance development. Using BRAF-mutant melanoma cell lines as the prototype, we report on a joint theoretical and experimental investigation of the cell-state transition dynamics associated with BRAF inhibitor drug tolerance. Thermodynamically motivated surprisal analysis of transcriptome data was used to treat the cell population as an entropy maximizing system under the influence of time-dependent constraints. This permits the extraction of an epigenetic potential landscape for drug-induced phenotypic evolution. Single-cell flow cytometry data of the same system were modeled with a modified Fokker-Planck-type kinetic model. The two approaches yield a consistent picture that accounts for the phenotypic heterogeneity observed over the course of drug tolerance development. The results reveal that, in certain plastic cancers, the population heterogeneity and evolution of cell phenotypes may be understood by accounting for the competing interactions of the epigenetic potential landscape and state-dependent cell proliferation. Accounting for such competition permits accurate, experimentally verifiable predictions that can potentially guide the design of effective treatment strategies.
Pubmed ID: 31166947 RIS Download
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Multi paradigm numerical computing environment and fourth generation programming language developed by MathWorks. Allows matrix manipulations, plotting of functions and data, implementation of algorithms, creation of user interfaces, and interfacing with programs written in other languages, including C, C++, Java, Fortran and Python. Used to explore and visualize ideas and collaborate across disciplines including signal and image processing, communications, control systems, and computational finance.
View all literature mentionsSoftware platform for complex network analysis and visualization. Used for visualization of molecular interaction networks and biological pathways and integrating these networks with annotations, gene expression profiles and other state data.
View all literature mentionsSoftware package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.
View all literature mentionsSoftware for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.
View all literature mentionsA program that opens a new perspective to the analysis of microarray data (e.g., gene expression profiling). Unlike traditional gene clustering software, GEDI is primarily sample-oriented rather than gene-oriented. By treating each high-dimensional sample, such as one microarray experiment, as an object, it accentuates the genome-wide response of a tissue or a patient and treats it as an integrated biological entity. Hence, GEDI honors the new spirit of a system-level approach in biology. Yet, it also allows the researcher to quickly zoom-in from global patterns onto individual genes that exhibit interesting expression behavior and retrieve gene-specific information. Therefore, GEDI unites a novel holistic perspective with the traditional gene-centered approach in molecular biology. GEDI allows experimental biologists or clinicians with no bioinformatics background to efficiently and intuitively navigate through a large number of expression profiles, each with a memorizable face, and inspect, group and collect them, like managing a stack of baseball cards. DYNAMIC ANALYSIS: The unique strength of GEDI, for which GEDI was originally developed, is that it can display the results of parallel monitoring of multiple high-dimensional time courses, such as the comparison of expression profile time evolution in response to a series of drugs. GEDI creates animated graphics showing how 10,000s of genes change their expression over time in response to 100s of separately tested drugs. STATIC ANAYLSIS: The signature graphical output of GEDI, the GEDI-mosaics provide a unique, one-glance visual engram that gives each microarray or other high-dimensional dataset a face. A characteristic of GEDI''s analysis is that it does not prejudicate any particular structure in the data (such as clusters or hierarchical organization). Thus, it allows the researcher to use human pattern recognition to perform a global first-level analysis of the data. Sponsor. The project was supported by the Air Force Office of Scientific Research and the National Health Institutes. It is distributed for free academic use by the Childrens Hospital, Boston.
View all literature mentionsA commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.
View all literature mentionsSoftware tool for transcriptome assembly and differential expression analysis for RNA-Seq. Includes script called cuffmerge that can be used to merge together several Cufflinks assemblies. It also handles running Cuffcompare as well as automatically filtering a number of transfrags that are likely to be artifacts. If the researcher has a reference GTF file, the researcher can provide it to the script to more effectively merge novel isoforms and maximize overall assembly quality.
View all literature mentionsThis polyclonal targets Human/Mouse/Rat N-Cadherin Affinity Purified Ab
View all literature mentionsThis polyclonal targets Mouse IgG (H+L)
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View all literature mentionsThis monoclonal targets CD271
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