Descrizione del progetto
Trascrizioni telomeriche in cellule di osteosarcoma con un allungamento alternativo dei telomeri
La capacità di replicazione delle cellule cancerose è legata alla loro capacità di rinnovare le estremità dei loro cromosomi, i cosiddetti telomeri. Alcuni carcinomi utilizzano un percorso alternativo per l’allungamento dei propri telomeri (ALT, Alternative Lengthening of Telomeres). Le cellule ALT mostrano livelli aumentati di TERRA (TElomeric Repeat-containing RNA), una lunga molecola di RNA non codificante trascritta dai telomeri. Studi preliminari suggeriscono che TERRA sia presente nelle cellule di osteosarcoma ALT-positive dell’uomo, dove l’infiammazione è associata a prognosi infausta e metastasi. Il progetto CytoTERRA, finanziato dall’UE, verificherà l’ipotesi che l’accumulo di TERRA citoplasmatico (cyTERRA) sia indotto da danni al DNA telomerico e sia in grado di avviare una risposta infiammatoria. Comprendere la funzione del cyTERRA nell’osteosarcoma ALT consentirà di utilizzarlo come marcatore dell’infiammazione e di introdurre il suo percorso come bersaglio terapeutico.
Obiettivo
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.
Campo scientifico
- natural sciencesbiological sciencesgeneticsDNA
- natural sciencesbiological sciencescell biology
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensors
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesgeneticschromosomes
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
38122 Trento
Italia