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Las neuronas liberan serina para apoyar la traducción de ARNm en el cáncer de páncreas
Robert S Banh1, Douglas E Biancur1, Keisuke Yamamoto1
1Department of Radiation Oncology, Perlmutter Cancer Center, New York University Medical Center, New York, NY 10016, USA.
Cell
|November 3, 2020
Resumen
Los axones periféricos suministran serina a las células de cáncer de páncreas, alimentando el crecimiento tumoral en entornos pobres en nutrientes. El bloqueo del factor de crecimiento nervioso inhibe aún más la progresión del adenocarcinoma ductal pancreático.
Área de la Ciencia:
- En el campo de la oncología
- La neurociencia
- El metabolismo
Sus antecedentes:
- Los tumores de adenocarcinoma ductal pancreático (PDAC) existen en un microambiente pobre en nutrientes, desmoplástico e innervado.
- Mientras que las neuronas liberan factores que promueven el PDAC, el papel metabólico de los axones periféricos sigue sin explorarse.
Objetivo del estudio:
- Investigar la contribución metabólica de los axones periféricos al crecimiento del PDAC.
- Explorar la interacción entre la liberación de serina axonal y la adaptación de las células PDAC a la privación de nutrientes.
Principales métodos:
- Evaluación de la liberación de serina (Ser) desde los axones periféricos.
- Se estudió el crecimiento de las células PDAC bajo privación de Ser/Gly.
- Se analizó el estancamiento ribosomal en los codones Ser y la secreción del factor de crecimiento nervioso (NGF).
- Se utilizaron modelos de ratón con tumores PDAC en una dieta libre de Ser/Gly.
- Se administró LOXO-101, un inhibidor de Trk-NGF, para bloquear la inervación neuronal.
Principales resultados:
- Los axones periféricos liberan serina, apoyando las células PDAC exógenas dependientes de Ser (exSer) durante la privación de Ser / Gly.
- La privación de serina indujo el estancamiento ribosomal en codones Ser específicos (TCC, TCT), promoviendo la traducción y secreción selectiva de NGF por parte de las células PDAC.
- Los tumores PDAC crecieron más lentamente con una mayor inervación en ratones con una dieta libre de Ser/ Gly.
- La inhibición de la señalización de NGF con LOXO-101 redujo aún más el crecimiento tumoral de PDAC.
Conclusiones:
- El cruce metabólico axonal-cáncer es crucial para la adaptación y el crecimiento de PDAC en condiciones pobres en nutrientes.
- El suministro de serina de los axones y la inervación mediada por NGF son componentes clave de este cruce.
- La orientación de la señalización NGF presenta una estrategia terapéutica potencial para el PDAC.
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