Descripción del proyecto
Transcripción telomérica en las células de osteosarcoma con un alargamiento alternativo de los telómeros
La capacidad de replicación de las células cancerosas está vinculada a su habilidad para renovar los finales de sus cromosomas, llamados telómeros. Algunos tipos de cáncer utilizan una ruta de alargamiento alternativo de los telómeros (ALT) para mantener los suyos. Las células con ALT muestran unos niveles mayores de TERRA, un ARN no codificante de cadena larga transcrito en los telómeros. Estudios preliminares sugieren que el TERRA está presente en las células humanas con ALT del osteosarcoma, en el que la inflamación se asocia con un mal pronóstico y metástasis. El proyecto financiado con fondos europeos CytoTERRA pondrá a prueba la hipótesis de que la acumulación de TERRA citoplasmático es inducida por el daño en el ADN telomérico y es capaz de iniciar una respuesta inflamatoria. Comprender la función del TERRA citoplasmático en el ALT del osteosarcoma permitirá que se use como marcador de la inflamación e introducir su ruta como diana terapéutica.
Objetivo
The unlimited replication potential of cancer cells is enabled by their ability to renew their ends of chromosomes, telomeres. A minority of cancers utilizes a recombination pathway, named alternative lenghtening of telomeres (ALT), to maintain their telomeres. ALT cells exhibit increased DNA damage at telomeres and increased levels of TERRA, a lncRNA transcribed from telomeres. TERRA plays important roles in telomere biology, but it also has extranuclear functions. Short TERRA species were found in extracellular vesicles of lymphoblastoid and cancer cells, and they were found to stimulate inflammation. Notably, inflammation can have both anti-tumorigenic and pro-tumorigenic effects. Particularly, in osteosarcoma, a bone cancer with high ALT incidence, affecting predominantly children and adolescents, inflammation is connected to poor prognosis and metastasis development.
Our preliminary results suggest that TERRA is present in the cytoplasm of human ALT osteosarcoma cells. We propose that the accumulation of cytoplasmic TERRA (cyTERRA) is induced by telomeric DNA damage, and that cyTERRA, similarly to extracellular TERRA, is capable of initiating an inflammation response. Since the cytoplasmic DNA sensor pathway is defective in these cells, we propose that TERRA plays a role of a DNA damage messenger that triggers the pro-tumorigenic inflammation.
We will test our hypothesis by studying the characteristics of cyTERRA, elucidating the factors influencing its localization and studying the effect of cyTERRA depletion on inflammation signalling in these cells.
The understanding of the function of cyTERRA in ALT osteosarcoma may introduce it as a marker for inflammation, and expose its export pathway as a therapeutic target. Since the variability of therapeutic outcome in osteosarcoma patients is not completely understood, the understanding of cancer inflammation triggers may be valuable for personalized therapeutic approach in these patients.
Ámbito científico
- natural sciencesbiological sciencesgeneticsDNA
- natural sciencesbiological sciencescell biology
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensors
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesgeneticschromosomes
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
38122 Trento
Italia