CytoTERRA · Elucidating the function of telomeric transcripts in the cytoplasm of ALT osteosarcoma cells
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-09-01 → 2023-08-31
- EU contribution
- €171,473
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Elucidating the function of telomeric transcripts in the cytoplasm of ALT osteosarcoma cells
The project—CytoTERRA—aimed to understand a curious phenomenon present in ALT cancers— a subset of cancers that share a common molecular trait. In general, cancer cells achieve immortality by re-activating a particular enzyme, telomerase, that lengthens their chromosome ends (telomeres) and in this way, grants them the unlimited capacity for proliferation. ALT cancers bypass the need for the reactivation of telomerase, and they achieve immortality by recombining their chromosome ends—the short ones are then elongated using the longer ones. Cancer cells of this molecular type can be present in many tumor types, very often in cancers arising from soft tissues, such as bone cancer or certain children's brain cancers. The peculiar characteristic we have noticed and studied is that in ALT cancers, one molecular component typically present at chromosome ends, an RNA molecule called TERRA, is not present in the nucleus, as has been described before, but surprisingly, also outside of the nucleus, in the cytoplasm. Such an unusual observation may turn out to be important for cancer treatment or diagnosis—if we discovered that cytoplasmic TERRA (or cytoTERRA) helps the survival of ALT cancer cells, it could be attempted to target it for degradation or block its function, in other words, use it as a therapeutic target. Alternatively, cytoTERRA could turn out to be a reliable and easily detectable hallmark of ALT cancers—speeding up diagnosis and the selection of appropriate treatment regimen. To open these possibilities, in this project, our objective was to understand what conditions drive TERRA to the cytoplasm, what are the cellular components enabling such transport and elucidate the processes in which cytoTERRA is involved.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- UNIVERSITA DEGLI STUDI DI TRENTO · TrentoCoordinatorItaly
Links
- View on CORDIS
- DOI: 10.3030/101032702
- https://www.cibio.unitn.it/501/laboratory-of-cell-biology-and-molecular-genetics
Data: CORDIS, © European Union