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1.
Brief Bioinform ; 23(1)2022 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-34619769

RESUMEN

Ordinary differential equation models are nowadays widely used for the mechanistic description of biological processes and their temporal evolution. These models typically have many unknown and nonmeasurable parameters, which have to be determined by fitting the model to experimental data. In order to perform this task, known as parameter estimation or model calibration, the modeller faces challenges such as poor parameter identifiability, lack of sufficiently informative experimental data and the existence of local minima in the objective function landscape. These issues tend to worsen with larger model sizes, increasing the computational complexity and the number of unknown parameters. An incorrectly calibrated model is problematic because it may result in inaccurate predictions and misleading conclusions. For nonexpert users, there are a large number of potential pitfalls. Here, we provide a protocol that guides the user through all the steps involved in the calibration of dynamic models. We illustrate the methodology with two models and provide all the code required to reproduce the results and perform the same analysis on new models. Our protocol provides practitioners and researchers in biological modelling with a one-stop guide that is at the same time compact and sufficiently comprehensive to cover all aspects of the problem.


Asunto(s)
Modelos Biológicos , Biología de Sistemas , Calibración , Biología de Sistemas/métodos
2.
Bioinformatics ; 39(11)2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37995297

RESUMEN

SUMMARY: Mechanistic models are important tools to describe and understand biological processes. However, they typically rely on unknown parameters, the estimation of which can be challenging for large and complex systems. pyPESTO is a modular framework for systematic parameter estimation, with scalable algorithms for optimization and uncertainty quantification. While tailored to ordinary differential equation problems, pyPESTO is broadly applicable to black-box parameter estimation problems. Besides own implementations, it provides a unified interface to various popular simulation and inference methods. AVAILABILITY AND IMPLEMENTATION: pyPESTO is implemented in Python, open-source under a 3-Clause BSD license. Code and documentation are available on GitHub (https://github.com/icb-dcm/pypesto).


Asunto(s)
Algoritmos , Programas Informáticos , Simulación por Computador , Incertidumbre , Documentación , Modelos Biológicos
3.
Mol Syst Biol ; 19(2): e10988, 2023 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-36700386

RESUMEN

BRAF is prototypical of oncogenes that can be targeted therapeutically and the treatment of BRAFV600E melanomas with RAF and MEK inhibitors results in rapid tumor regression. However, drug-induced rewiring generates a drug adapted state thought to be involved in acquired resistance and disease recurrence. In this article, we study mechanisms of adaptive rewiring in BRAFV600E melanoma cells using an energy-based implementation of ordinary differential equation (ODE) modeling in combination with proteomic, transcriptomic and imaging data. We develop a method for causal tracing of ODE models and identify two parallel MAPK reaction channels that are differentially sensitive to RAF and MEK inhibitors due to differences in protein oligomerization and drug binding. We describe how these channels, and timescale separation between immediate-early signaling and transcriptional feedback, create a state in which the RAS-regulated MAPK channel can be activated by growth factors under conditions in which the BRAFV600E -driven channel is fully inhibited. Further development of the approaches in this article is expected to yield a unified model of adaptive drug resistance in melanoma.


Asunto(s)
Melanoma , Proteínas Proto-Oncogénicas B-raf , Humanos , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Sistema de Señalización de MAP Quinasas , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/uso terapéutico , Mutación , Recurrencia Local de Neoplasia , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteómica , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo
4.
PLoS Comput Biol ; 19(1): e1010783, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36595539

RESUMEN

Dynamical models in the form of systems of ordinary differential equations have become a standard tool in systems biology. Many parameters of such models are usually unknown and have to be inferred from experimental data. Gradient-based optimization has proven to be effective for parameter estimation. However, computing gradients becomes increasingly costly for larger models, which are required for capturing the complex interactions of multiple biochemical pathways. Adjoint sensitivity analysis has been pivotal for working with such large models, but methods tailored for steady-state data are currently not available. We propose a new adjoint method for computing gradients, which is applicable if the experimental data include steady-state measurements. The method is based on a reformulation of the backward integration problem to a system of linear algebraic equations. The evaluation of the proposed method using real-world problems shows a speedup of total simulation time by a factor of up to 4.4. Our results demonstrate that the proposed approach can achieve a substantial improvement in computation time, in particular for large-scale models, where computational efficiency is critical.


Asunto(s)
Modelos Biológicos , Biología de Sistemas , Simulación por Computador , Biología de Sistemas/métodos , Algoritmos
5.
Nucleic Acids Res ; 50(W1): W108-W114, 2022 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-35524558

RESUMEN

Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed through a distinct interface. To help investigators find and use simulation tools, we developed BioSimulators (https://biosimulators.org), a central registry of the capabilities of simulation tools and consistent Python, command-line and containerized interfaces to each version of each tool. The foundation of BioSimulators is standards, such as CellML, SBML, SED-ML and the COMBINE archive format, and validation tools for simulation projects and simulation tools that ensure these standards are used consistently. To help modelers find tools for particular projects, we have also used the registry to develop recommendation services. We anticipate that BioSimulators will help modelers exchange, reproduce, and combine simulations.


Asunto(s)
Simulación por Computador , Programas Informáticos , Humanos , Bioingeniería , Modelos Biológicos , Sistema de Registros , Investigadores
6.
PLoS Comput Biol ; 18(7): e1010322, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35830470

RESUMEN

Ordinary differential equation (ODE) models are widely used to study biochemical reactions in cellular networks since they effectively describe the temporal evolution of these networks using mass action kinetics. The parameters of these models are rarely known a priori and must instead be estimated by calibration using experimental data. Optimization-based calibration of ODE models on is often challenging, even for low-dimensional problems. Multiple hypotheses have been advanced to explain why biochemical model calibration is challenging, including non-identifiability of model parameters, but there are few comprehensive studies that test these hypotheses, likely because tools for performing such studies are also lacking. Nonetheless, reliable model calibration is essential for uncertainty analysis, model comparison, and biological interpretation. We implemented an established trust-region method as a modular Python framework (fides) to enable systematic comparison of different approaches to ODE model calibration involving a variety of Hessian approximation schemes. We evaluated fides on a recently developed corpus of biologically realistic benchmark problems for which real experimental data are available. Unexpectedly, we observed high variability in optimizer performance among different implementations of the same mathematical instructions (algorithms). Analysis of possible sources of poor optimizer performance identified limitations in the widely used Gauss-Newton, BFGS and SR1 Hessian approximation schemes. We addressed these drawbacks with a novel hybrid Hessian approximation scheme that enhances optimizer performance and outperforms existing hybrid approaches. When applied to the corpus of test models, we found that fides was on average more reliable and efficient than existing methods using a variety of criteria. We expect fides to be broadly useful for ODE constrained optimization problems in biochemical models and to be a foundation for future methods development.


Asunto(s)
Modelos Biológicos , Confianza , Algoritmos , Cinética , Incertidumbre
7.
Bioinformatics ; 37(20): 3676-3677, 2021 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-33821950

RESUMEN

SUMMARY: Ordinary differential equation models facilitate the understanding of cellular signal transduction and other biological processes. However, for large and comprehensive models, the computational cost of simulating or calibrating can be limiting. AMICI is a modular toolbox implemented in C++/Python/MATLAB that provides efficient simulation and sensitivity analysis routines tailored for scalable, gradient-based parameter estimation and uncertainty quantification. AVAILABILITYAND IMPLEMENTATION: AMICI is published under the permissive BSD-3-Clause license with source code publicly available on https://github.com/AMICI-dev/AMICI. Citeable releases are archived on Zenodo. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

8.
PLoS Comput Biol ; 17(12): e1009689, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34962919

RESUMEN

The design of efficient combination therapies is a difficult key challenge in the treatment of complex diseases such as cancers. The large heterogeneity of cancers and the large number of available drugs renders exhaustive in vivo or even in vitro investigation of possible treatments impractical. In recent years, sophisticated mechanistic, ordinary differential equation-based pathways models that can predict treatment responses at a molecular level have been developed. However, surprisingly little effort has been put into leveraging these models to find novel therapies. In this paper we use for the first time, to our knowledge, a large-scale state-of-the-art pan-cancer signaling pathway model to identify candidates for novel combination therapies to treat individual cancer cell lines from various tissues (e.g., minimizing proliferation while keeping dosage low to avoid adverse side effects) and populations of heterogeneous cancer cell lines (e.g., minimizing the maximum or average proliferation across the cell lines while keeping dosage low). We also show how our method can be used to optimize the drug combinations used in sequential treatment plans-that is, optimized sequences of potentially different drug combinations-providing additional benefits. In order to solve the treatment optimization problems, we combine the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) algorithm with a significantly more scalable sampling scheme for truncated Gaussian distributions, based on a Hamiltonian Monte-Carlo method. These optimization techniques are independent of the signaling pathway model, and can thus be adapted to find treatment candidates for other complex diseases than cancers as well, as long as a suitable predictive model is available.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Algoritmos , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proliferación Celular/efectos de los fármacos , Biología Computacional , Toma de Decisiones Asistida por Computador , Humanos
9.
PLoS Comput Biol ; 17(1): e1008646, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33497393

RESUMEN

Reproducibility and reusability of the results of data-based modeling studies are essential. Yet, there has been-so far-no broadly supported format for the specification of parameter estimation problems in systems biology. Here, we introduce PEtab, a format which facilitates the specification of parameter estimation problems using Systems Biology Markup Language (SBML) models and a set of tab-separated value files describing the observation model and experimental data as well as parameters to be estimated. We already implemented PEtab support into eight well-established model simulation and parameter estimation toolboxes with hundreds of users in total. We provide a Python library for validation and modification of a PEtab problem and currently 20 example parameter estimation problems based on recent studies.


Asunto(s)
Lenguajes de Programación , Biología de Sistemas/métodos , Algoritmos , Bases de Datos Factuales , Modelos Biológicos , Modelos Estadísticos , Reproducibilidad de los Resultados
10.
Bioinformatics ; 36(2): 594-602, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31347657

RESUMEN

MOTIVATION: Mechanistic models of biochemical reaction networks facilitate the quantitative understanding of biological processes and the integration of heterogeneous datasets. However, some biological processes require the consideration of comprehensive reaction networks and therefore large-scale models. Parameter estimation for such models poses great challenges, in particular when the data are on a relative scale. RESULTS: Here, we propose a novel hierarchical approach combining (i) the efficient analytic evaluation of optimal scaling, offset and error model parameters with (ii) the scalable evaluation of objective function gradients using adjoint sensitivity analysis. We evaluate the properties of the methods by parameterizing a pan-cancer ordinary differential equation model (>1000 state variables, >4000 parameters) using relative protein, phosphoprotein and viability measurements. The hierarchical formulation improves optimizer performance considerably. Furthermore, we show that this approach allows estimating error model parameters with negligible computational overhead when no experimental estimates are available, providing an unbiased way to weight heterogeneous data. Overall, our hierarchical formulation is applicable to a wide range of models, and allows for the efficient parameterization of large-scale models based on heterogeneous relative measurements. AVAILABILITY AND IMPLEMENTATION: Supplementary code and data are available online at http://doi.org/10.5281/zenodo.3254429 and http://doi.org/10.5281/zenodo.3254441. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Modelos Biológicos , Programas Informáticos , Algoritmos , Proyectos de Investigación
11.
Bioinformatics ; 35(5): 830-838, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30816929

RESUMEN

MOTIVATION: Kinetic models contain unknown parameters that are estimated by optimizing the fit to experimental data. This task can be computationally challenging due to the presence of local optima and ill-conditioning. While a variety of optimization methods have been suggested to surmount these issues, it is difficult to choose the best one for a given problem a priori. A systematic comparison of parameter estimation methods for problems with tens to hundreds of optimization variables is currently missing, and smaller studies provided contradictory findings. RESULTS: We use a collection of benchmarks to evaluate the performance of two families of optimization methods: (i) multi-starts of deterministic local searches and (ii) stochastic global optimization metaheuristics; the latter may be combined with deterministic local searches, leading to hybrid methods. A fair comparison is ensured through a collaborative evaluation and a consideration of multiple performance metrics. We discuss possible evaluation criteria to assess the trade-off between computational efficiency and robustness. Our results show that, thanks to recent advances in the calculation of parametric sensitivities, a multi-start of gradient-based local methods is often a successful strategy, but a better performance can be obtained with a hybrid metaheuristic. The best performer combines a global scatter search metaheuristic with an interior point local method, provided with gradients estimated with adjoint-based sensitivities. We provide an implementation of this method to render it available to the scientific community. AVAILABILITY AND IMPLEMENTATION: The code to reproduce the results is provided as Supplementary Material and is available at Zenodo https://doi.org/10.5281/zenodo.1304034. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Benchmarking , Programas Informáticos , Algoritmos , Cinética , Modelos Biológicos
13.
Bioinformatics ; 34(13): i151-i159, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29949990

RESUMEN

Motivation: Parameter estimation methods for ordinary differential equation (ODE) models of biological processes can exploit gradients and Hessians of objective functions to achieve convergence and computational efficiency. However, the computational complexity of established methods to evaluate the Hessian scales linearly with the number of state variables and quadratically with the number of parameters. This limits their application to low-dimensional problems. Results: We introduce second order adjoint sensitivity analysis for the computation of Hessians and a hybrid optimization-integration-based approach for profile likelihood computation. Second order adjoint sensitivity analysis scales linearly with the number of parameters and state variables. The Hessians are effectively exploited by the proposed profile likelihood computation approach. We evaluate our approaches on published biological models with real measurement data. Our study reveals an improved computational efficiency and robustness of optimization compared to established approaches, when using Hessians computed with adjoint sensitivity analysis. The hybrid computation method was more than 2-fold faster than the best competitor. Thus, the proposed methods and implemented algorithms allow for the improvement of parameter estimation for medium and large scale ODE models. Availability and implementation: The algorithms for second order adjoint sensitivity analysis are implemented in the Advanced MATLAB Interface to CVODES and IDAS (AMICI, https://github.com/ICB-DCM/AMICI/). The algorithm for hybrid profile likelihood computation is implemented in the parameter estimation toolbox (PESTO, https://github.com/ICB-DCM/PESTO/). Both toolboxes are freely available under the BSD license. Supplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Biología Computacional/métodos , Modelos Biológicos , Programas Informáticos , Algoritmos , Probabilidad
14.
Bioinformatics ; 34(8): 1421-1423, 2018 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-29206901

RESUMEN

Motivation: Mathematical modeling using ordinary differential equations is used in systems biology to improve the understanding of dynamic biological processes. The parameters of ordinary differential equation models are usually estimated from experimental data. To analyze a priori the uniqueness of the solution of the estimation problem, structural identifiability analysis methods have been developed. Results: We introduce GenSSI 2.0, an advancement of the software toolbox GenSSI (Generating Series for testing Structural Identifiability). GenSSI 2.0 is the first toolbox for structural identifiability analysis to implement Systems Biology Markup Language import, state/parameter transformations and multi-experiment structural identifiability analysis. In addition, GenSSI 2.0 supports a range of MATLAB versions and is computationally more efficient than its previous version, enabling the analysis of more complex models. Availability and implementation: GenSSI 2.0 is an open-source MATLAB toolbox and available at https://github.com/genssi-developer/GenSSI. Contact: thomas.ligon@physik.uni-muenchen.de or jan.hasenauer@helmholtz-muenchen.de. Supplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Modelos Biológicos , Programas Informáticos , Biología de Sistemas/métodos
15.
Bioinformatics ; 34(4): 705-707, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29069312

RESUMEN

Summary: PESTO is a widely applicable and highly customizable toolbox for parameter estimation in MathWorks MATLAB. It offers scalable algorithms for optimization, uncertainty and identifiability analysis, which work in a very generic manner, treating the objective function as a black box. Hence, PESTO can be used for any parameter estimation problem, for which the user can provide a deterministic objective function in MATLAB. Availability and implementation: PESTO is a MATLAB toolbox, freely available under the BSD license. The source code, along with extensive documentation and example code, can be downloaded from https://github.com/ICB-DCM/PESTO/. Contact: jan.hasenauer@helmholtz-muenchen.de. Supplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Biología Computacional/métodos , Programas Informáticos , Algoritmos
16.
Bioinformatics ; 33(7): 1049-1056, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28040696

RESUMEN

Motivation: Ordinary differential equation (ODE) models are frequently used to describe the dynamic behaviour of biochemical processes. Such ODE models are often extended by events to describe the effect of fast latent processes on the process dynamics. To exploit the predictive power of ODE models, their parameters have to be inferred from experimental data. For models without events, gradient based optimization schemes perform well for parameter estimation, when sensitivity equations are used for gradient computation. Yet, sensitivity equations for models with parameter- and state-dependent events and event-triggered observations are not supported by existing toolboxes. Results: In this manuscript, we describe the sensitivity equations for differential equation models with events and demonstrate how to estimate parameters from event-resolved data using event-triggered observations in parameter estimation. We consider a model for GFP expression after transfection and a model for spiking neurons and demonstrate that we can improve computational efficiency and robustness of parameter estimation by using sensitivity equations for systems with events. Moreover, we demonstrate that, by using event-outputs, it is possible to consider event-resolved data, such as time-to-event data, for parameter estimation with ODE models. By providing a user-friendly, modular implementation in the toolbox AMICI, the developed methods are made publicly available and can be integrated in other systems biology toolboxes. Availability and Implementation: We implement the methods in the open-source toolbox Advanced MATLAB Interface for CVODES and IDAS (AMICI, https://github.com/ICB-DCM/AMICI ). Contact: jan.hasenauer@helmholtz-muenchen.de. Supplementary information: Supplementary data are available at Bioinformatics online.


Asunto(s)
Modelos Biológicos , Programas Informáticos , Biología Computacional/métodos , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Potenciales de la Membrana , Neuronas/fisiología , Biología de Sistemas , Transfección
17.
PLoS Comput Biol ; 13(1): e1005331, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28114351

RESUMEN

Mechanistic mathematical modeling of biochemical reaction networks using ordinary differential equation (ODE) models has improved our understanding of small- and medium-scale biological processes. While the same should in principle hold for large- and genome-scale processes, the computational methods for the analysis of ODE models which describe hundreds or thousands of biochemical species and reactions are missing so far. While individual simulations are feasible, the inference of the model parameters from experimental data is computationally too intensive. In this manuscript, we evaluate adjoint sensitivity analysis for parameter estimation in large scale biochemical reaction networks. We present the approach for time-discrete measurement and compare it to state-of-the-art methods used in systems and computational biology. Our comparison reveals a significantly improved computational efficiency and a superior scalability of adjoint sensitivity analysis. The computational complexity is effectively independent of the number of parameters, enabling the analysis of large- and genome-scale models. Our study of a comprehensive kinetic model of ErbB signaling shows that parameter estimation using adjoint sensitivity analysis requires a fraction of the computation time of established methods. The proposed method will facilitate mechanistic modeling of genome-scale cellular processes, as required in the age of omics.


Asunto(s)
Regulación de la Expresión Génica/fisiología , Genoma/fisiología , Modelos Biológicos , Modelos Estadísticos , Proteoma/metabolismo , Transducción de Señal/fisiología , Simulación por Computador , Lenguajes de Programación , Programas Informáticos
18.
PLoS Comput Biol ; 12(7): e1005030, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27447730

RESUMEN

Quantitative mechanistic models are valuable tools for disentangling biochemical pathways and for achieving a comprehensive understanding of biological systems. However, to be quantitative the parameters of these models have to be estimated from experimental data. In the presence of significant stochastic fluctuations this is a challenging task as stochastic simulations are usually too time-consuming and a macroscopic description using reaction rate equations (RREs) is no longer accurate. In this manuscript, we therefore consider moment-closure approximation (MA) and the system size expansion (SSE), which approximate the statistical moments of stochastic processes and tend to be more precise than macroscopic descriptions. We introduce gradient-based parameter optimization methods and uncertainty analysis methods for MA and SSE. Efficiency and reliability of the methods are assessed using simulation examples as well as by an application to data for Epo-induced JAK/STAT signaling. The application revealed that even if merely population-average data are available, MA and SSE improve parameter identifiability in comparison to RRE. Furthermore, the simulation examples revealed that the resulting estimates are more reliable for an intermediate volume regime. In this regime the estimation error is reduced and we propose methods to determine the regime boundaries. These results illustrate that inference using MA and SSE is feasible and possesses a high sensitivity.


Asunto(s)
Modelos Biológicos , Modelos Estadísticos , Transducción de Señal/fisiología , Análisis de la Célula Individual/métodos , Biología de Sistemas/métodos , Cinética , Procesos Estocásticos
19.
Methods Mol Biol ; 2634: 59-86, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37074574

RESUMEN

Aberrant signal transduction leads to complex diseases such as cancer. To rationally design treatment strategies with small molecule inhibitors, computational models have to be employed. Energy- and rule-based models allow the construction of mechanistic ordinary differential equation models based on structural insights. The detailed, energy-based description often generates large models, which are difficult to calibrate on experimental data. In this chapter, we provide a detailed, interactive protocol for the programmatic formulation and calibration of such large, energy- and rule-based models of cellular signal transduction based on an example model describing the action of RAF inhibitors on MAPK signaling. An interactive version of this chapter is available as Jupyter Notebook at github.com/FFroehlich/energy_modeling_chapter .


Asunto(s)
Modelos Biológicos , Transducción de Señal , Calibración , Transducción de Señal/fisiología
20.
Cell Rep ; 42(3): 112252, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36920903

RESUMEN

Oncogene-induced senescence is a phenomenon in which aberrant oncogene expression causes non-transformed cells to enter a non-proliferative state. Cells undergoing oncogenic induction display phenotypic heterogeneity, with some cells senescing and others remaining proliferative. The causes of heterogeneity remain unclear. We studied the sources of heterogeneity in the responses of human epithelial cells to oncogenic BRAFV600E expression. We found that a narrow expression range of BRAFV600E generated a wide range of activities of its downstream effector ERK. In population-level and single-cell assays, ERK activity displayed a non-monotonic relationship to proliferation, with intermediate ERK activities leading to maximal proliferation. We profiled gene expression across a range of ERK activities over time and characterized four distinct ERK response classes, which we propose act in concert to generate the ERK-proliferation response. Altogether, our studies map the input-output relationships between ERK activity and proliferation, elucidating how heterogeneity can be generated during oncogene induction.


Asunto(s)
Oncogenes , Proteínas Proto-Oncogénicas B-raf , Humanos , Línea Celular Tumoral , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo
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