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El análisis basado en árboles de trellis revela la regulación estromal de las respuestas orgánicas a los fármacos
María Ramos Zapatero1, Alexander Tong2, James W Opzoomer1
1Cell Communication Lab, Department of Oncology, University College London Cancer Institute, London WC1E 6DD, UK.
Cell
|December 8, 2023
Resumen
Desarrollamos una plataforma de citometría de masa y un método de análisis para estudiar los organoides del cáncer colorrectal (CRC) y su microambiente. Esto revela cómo los fibroblastos asociados al cáncer (CAF) protegen las células CRC de la quimioterapia al alterar los estados de las células madre.
Área de la Ciencia:
- En el campo de la oncología
- Biotecnología
- Biología celular
Sus antecedentes:
- Los organoides derivados de pacientes (DOP) son valiosos para modelar respuestas personalizadas a la terapia del cáncer.
- Los métodos de detección actuales carecen de la resolución para descubrir los mecanismos de los fármacos o la influencia de las células del microambiente tumoral en los resultados terapéuticos.
Objetivo del estudio:
- Desarrollar una plataforma de alto rendimiento para analizar los mecanismos de respuesta a los fármacos en las DOP de cáncer colorrectal (CRC) y sus células estromales asociadas.
- Investigar el impacto de los fibroblastos asociados al cáncer (CAF) en la plasticidad y la resistencia terapéutica de las células CRC.
Principales métodos:
- Utilizó una plataforma de citometría de masa altamente multiplexada para evaluar la señalización de la modificación post-traducional (PTM), el daño del ADN, el estado del ciclo celular y la apoptosis en >2,500 DOP y CAF de CRC.
- Desarrolló "Trellis", un método de análisis escalable basado en árboles para comparar las respuestas específicas del paciente y el microambiente a la resolución de una sola célula.
Principales resultados:
- El cribado de células individuales identificó efectos farmacológicos comunes en el objetivo, como el bloqueo del ciclo celular y el daño del ADN, incluso en las DOP resistentes a los medicamentos.
- Se encontró que la apoptosis inducida por fármacos es más rara, específica del paciente y correlacionada con la señalización PTM de las células cancerosas.
- Se ha demostrado que los CAF pueden inducir la plasticidad en las células madre CRC, cambiándolas de estados proliferativos (proCSC) a estados de ciclo lento (revCSC), lo que confiere resistencia a la quimioterapia.
Conclusiones:
- La plataforma desarrollada y el método Trellis permiten una visión mecánica profunda de las respuestas a los medicamentos dentro del complejo microambiente tumoral.
- La comprensión de los mecanismos de protección mediados por CAF es crucial para desarrollar nuevas estrategias terapéuticas contra el cáncer colorrectal quimiorresistente.
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