Projektbeschreibung
Telomertranskripte in Osteosarkomzellen mit alternativer Telomerverlängerung
Die Replikationskapazität von Krebszellen hängt mit ihrer Fähigkeit zusammen, die Enden ihrer Chromosomen, die sogenannten Telomere, erneuern zu können. Einige Krebsarten aktivieren einen Prozess namens alternative Telomerverlängerung (ALT), um ihre Telomere zu erhalten. ALT-Zellen weisen erhöhte TERRA-Anteile auf, einer langen, nichtkodierenden RNA, die von den Telomeren transkribiert wird. Vorläufige Studien deuten darauf hin, dass TERRA in humanen ALT-Osteosarkomzellen vorhanden ist, wobei Entzündungen mit einer schlechten Prognose und Metastasierung in Verbindung gebracht werden. Das EU-finanzierte Projekt CytoTERRA wird der Hypothese nachgehen, dass die Anhäufung zytoplasmatischer TERRA (cyTERRA) durch Telomer-DNA-Schäden ausgelöst wird und eine Entzündungsreaktion auslösen kann. Anhand des Verständnisses der Funktion von cyTERRA bei von ALT geprägten Osteosarkomen werden diese als Entzündungsmarker Einsatz finden. Zudem kann deren Signalweg als ein therapeutisches Ziel eingeführt werden.
Ziel
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.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesgeneticsDNA
- natural sciencesbiological sciencescell biology
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensors
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesgeneticschromosomes
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Aufforderung zur Vorschlagseinreichung
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
38122 Trento
Italien