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Diversificación intra-tumoral en el cáncer colorrectal a nivel de una sola célula
Sophie F Roerink1, Nobuo Sasaki2,3, Henry Lee-Six1
1Cancer Ageing and Somatic Mutations Programme, Wellcome Trust Sanger Insitute, Hinxton, UK.
Nature
|April 13, 2018
Resumen
Las células del cáncer colorrectal se diversifican significativamente más que las células normales, adquiriendo numerosas mutaciones y estados biológicos distintos. Esta heterogeneidad intra-tumoral impacta las respuestas a los fármacos, destacando el cáncer
Área de la Ciencia:
- Biología del cáncer
- La genómica
- La epigenética
Sus antecedentes:
- Los cánceres se originan en una sola célula, pero evolucionan en poblaciones heterogéneas.
- La comprensión de la diversificación intra-tumoral es crucial para el tratamiento eficaz del cáncer.
Objetivo del estudio:
- Investigar la diversificación genética y fenotípica dentro de los tumores colorrectales.
- Para comparar las tasas de mutación somática y los estados epigenéticos entre células cancerosas y normales.
- Evaluar el impacto de la heterogeneidad intra-tumoral en la respuesta al fármaco.
Principales métodos:
- Caracterización de organoides derivados de células individuales de cáncer colorrectal y tejidos normales adyacentes.
- Secuenciación de todo el genoma para identificar mutaciones somáticas.
- Análisis de la metilación del ADN y los estados del transcriptoma.
- Evaluación de las respuestas diferenciales al fármaco en organoides derivados de una sola célula.
Principales resultados:
- Las células de cáncer colorrectal mostraron una amplia diversificación mutacional, con un número significativamente mayor de mutaciones somáticas que las células normales.
- La mayoría de las mutaciones surgieron durante la expansión clonal en etapa tardía, impulsadas por procesos mutacionales distintos.
- Se observó heterogeneidad intra-tumoral en la metilación del ADN y los estados del transcriptoma, correlacionándose con la filogenia del cáncer.
- Las células cancerosas estrechamente relacionadas del mismo tumor mostraron marcadas diferencias en la sensibilidad al fármaco.
Conclusiones:
- Las células de cáncer colorrectal tienen tasas de mutación somática sustancialmente elevadas en comparación con las células normales.
- La diversificación genética se acompaña de diferencias estables y heredables en los estados celulares.
- La heterogeneidad intra-tumoral contribuye a las respuestas variables a los fármacos, lo que plantea desafíos para la terapia.
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