Elucidating the function of telomeric transcripts in the cytoplasm of ALT osteosarcoma cells

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.