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Análisis de divergencia de redes identifica módulos genéticos adaptativos y dos ejes ortogonales de vulnerabilidad en
Brian Nelson1, Lyanne Delgado-Coka2, Natalia Marchenko2
1Department of Applied Mathematics and Statistics, Stony Brook University, New York, NY, USA.
Molecular oncology
|March 2, 2026
Resumen
La adenocarcinoma ductal pancreático (CPAD) exhibe heterogeneidad transcripcional. Se identificaron cuatro módulos adaptativos (IGE, SAT, IL2, MPC), que revelan distintos programas regulatorios y relevancia clínica en la progresión del CPAD y la supervivencia del paciente.
Área de la Ciencia:
- Biología del Cáncer
- Genómica
- Biología Computacional
Sus antecedentes:
- El adenocarcinoma ductal pancreático (CPAD) muestra una heterogeneidad transcripcional significativa.
- Esta heterogeneidad surge tanto de cambios en la expresión génica como de la reorganización de la coordinación gen-gen.
Objetivo del estudio:
- Identificar y caracterizar módulos regulatorios adaptativos en el CPAD.
- Integrar estos módulos con datos de genómica funcional y respuesta a fármacos.
- Evaluar la relevancia clínica de estos módulos en el CPAD.
Principales métodos:
- Se aplicó un marco de aristas divergentes para analizar datos transcripcionales de 77.155 células malignas en 42 tumores de CPAD.
- Se integraron los módulos identificados con perfiles de dependencia de CRISPR-Cas9 y datos de respuesta a fármacos PRISM.
- Se correlacionó la actividad del módulo con los resultados clínicos, incluida la supervivencia del paciente.
Principales resultados:
- Se identificaron cuatro módulos adaptativos reproducibles: crecimiento-energía integrado (IGE), transcripción adaptativa al estrés (SAT), evasión inmune ligada a IL-2 (IL2) y invasión colectiva multirruta (MPC).
- Estos módulos se mapearon en dos ejes de orden superior: un eje IGE biosintético-metabólico y un eje SAT-IL2-MPC de estrés-inmune-invasión.
- Los tumores con SAT alto y MPC alto se correlacionaron con una peor supervivencia, definiendo un eje de mal pronóstico de estrés-inmune-invasión; la actividad del eje IGE mostró una asociación compleja con la supervivencia.
Conclusiones:
- La heterogeneidad transcripcional en el CPAD está estructurada por módulos adaptativos que reflejan distintos programas regulatorios.
- Los módulos y ejes identificados proporcionan información sobre la biología, las dependencias y las vulnerabilidades del CPAD.
- La actividad del módulo tiene relevancia clínica, con los módulos SAT y MPC indicando un mal pronóstico en el CPAD.
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