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La desregulación del ciclo de la urea genera firmas genómicas y bioquímicas clínicamente relevantes
Joo Sang Lee1, Lital Adler2, Hiren Karathia3
1Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, Department of Computer Science, University of Maryland, College Park, MD 20742, USA.
Cell
|August 14, 2018
Resumen
Las células cancerosas muestran desregulación del ciclo de urea (UCD), alterando el metabolismo del nitrógeno para estimular la síntesis de pirimidina. Este cambio metabólico impulsa mutaciones específicas y mejora la respuesta a la inmunoterapia en los tumores.
Área de la Ciencia:
- La bioquímica
- En el campo de la oncología
- Las vías metabólicas
Sus antecedentes:
- El ciclo de urea (UC) es crucial para la eliminación de residuos de nitrógeno en los mamíferos.
- La expresión alterada de la enzima UC se observa en numerosos tumores, definiendo una marca metabólica llamada desregulación de UC (UCD).
Objetivo del estudio:
- Para investigar las consecuencias metabólicas de la UCD en los tumores.
- Explorar el impacto de la UCD en las alteraciones genómicas y la respuesta a la inmunoterapia.
Principales métodos:
- Análisis de la expresión de la enzima UC en tumores.
- Perfiles metabólicos de los tumores y los biofluidos de los pacientes.
- Análisis genómico para identificar firmas de mutación.
- Correlación de la ECU con los antígenos tumorales y los resultados de la inmunoterapia.
Principales resultados:
- La UCD conduce a la desviación de nitrógeno, activando la CAD y mejorando la síntesis de pirimidina.
- Se detectan cambios claros en los metabolitos de nitrógeno en los tumores y en los biofluidos.
- La UCD induce una firma mutacional (mutaciones de transversión) y aumenta los antígenos hidrofóbicos del tumor.
- La UCD se asocia con una mejor respuesta a los inhibidores del punto de control inmunológico, independientemente de la carga mutacional.
Conclusiones:
- La UCD es una característica común en los tumores con implicaciones significativas para el desarrollo del cáncer.
- La UCD influye en la mutagénesis, creando un paisaje genómico que puede mejorar la inmunidad antitumoral.
- Dirigirse a la CDU o aprovechar sus efectos posteriores podría ofrecer nuevas estrategias terapéuticas en la inmunoterapia contra el cáncer.
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