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Respuestas celulares específicas del estado a fármacos asociadas con diferencias en la conectividad de redes de
Niels Krämer1, Roderick van Eijl2, Tim Stohn3
1Radboud Institute for Molecular Life Sciences, Faculty of Science, Department of Molecular Developmental Biology, Radboud University, Nijmegen, the Netherlands; Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm, Sweden.
Molecular & cellular proteomics : MCP
|February 18, 2026
Resumen
Las respuestas celulares a los tratamientos farmacológicos dependen del estado celular. Las interacciones de la red de señalización varían entre los estados celulares, lo que influye en cómo los fármacos afectan a las células. Comprender esta modulación del estado celular es clave para las terapias dirigidas.
Área de la Ciencia:
- Biología celular
- Biología de sistemas
- Farmacología
Sus antecedentes:
- Las vías de señalización intracelular transmiten información a través de la fosforilación mediada por quinasas.
- Existe heterogeneidad celular en el estado y la respuesta de señalización incluso en células isogénicas.
- Comprender la señalización dependiente del estado celular es crucial para el desarrollo de fármacos.
Objetivo del estudio:
- Investigar el flujo de información en la red del receptor EGF bajo tratamiento farmacológico.
- Determinar cómo las diferencias en el estado celular de célula a célula afectan las vías de señalización.
- Elucidar la relación entre el estado celular, la respuesta a fármacos y la dinámica de la red de señalización.
Principales métodos:
- Se utilizó ID-seq de célula única para perfilar el estado celular y la actividad de señalización.
- Se midieron 69 (fosfo-)proteínas en células madre epidérmicas humanas primarias.
- Se inhibieron las vías Erk/MAPK (p90RSK) y Akt/mTOR (p70S6K) aguas abajo de EGF.
- Se empleó la Reconstrucción Comparativa de Redes de Célula Única para el modelado computacional.
Principales resultados:
- Los efectos del tratamiento farmacológico se propagaron a través de la red de señalización EGF, alterando el flujo de señalización.
- Se identificaron nueve estados celulares distintos con respuestas a fármacos dependientes del estado para múltiples (fosfo-)proteínas.
- El modelado computacional reveló diferencias específicas del estado celular en las interacciones de la red de señalización (conectividad de la red).
- Las (fosfo-)proteínas con respuestas a fármacos dependientes del estado se vincularon con fortalezas de interacción dependientes del estado.
Conclusiones:
- Las respuestas al tratamiento farmacológico están estrechamente relacionadas con las interacciones de señalización entre proteínas.
- El estado celular modula significativamente tanto la respuesta a fármacos como la fuerza de las interacciones proteicas.
- Estos hallazgos resaltan la importancia de considerar la heterogeneidad del estado celular en la eficacia de los fármacos y el análisis de redes de señalización.
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