Periodic Reporting for period 1 - CytoTERRA (Elucidating the function of telomeric transcripts in the cytoplasm of ALT osteosarcoma cells)
Reporting period: 2021-09-01 to 2023-08-31
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.
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.
In the course of our project, we have described the conditions under which cytoTERRA levels increase, and started to study its connection to DNA damage accumulation that is typical for ALT cancer cells. Combining proteomics and bioinformatics analysis, we described the protein interaction partners of cytoTERRA. We did not acquire results supporting our initial hypothesis, that cytoTERRA may be involved in inflammation stimulation in ALT cancers, and in collaboration with three other scientific groups, gained support for the possibility that instead, it participates in translation regulation and stress response, including stress granule formation. We are currently exploring what proteins are involved in its nuclear export (with a protein called NXF1 as a candidate) and whether the formation of secondary structures on the RNA molecule, such as RNA G-quadruplexes, may have a role in its cytoplasmic function. In addition, together with the host laboratory, we were the first to study and describe TERRA in the nematode C. elegans that is an important animal model of ALT cancers.
We have introduced and discussed the acquired results with the peers in the field, through the participation in 3 scientific conferences and publication of one peer-review article, with two other manuscripts in preparation.
We have introduced and discussed the acquired results with the peers in the field, through the participation in 3 scientific conferences and publication of one peer-review article, with two other manuscripts in preparation.
In our work, we set the basis for understanding the function of cytoTERRA as a potential effector in stress response to DNA damage in ALT cells, still surveying the possibility of cytoTERRA being involved in the intercellular signaling of cancer stress response.
The results we have acquired on cytoTERRA add to the emerging picture in the field of telomere biology that TERRA, beyond its roles at chromosome ends and in the nucleus, may serve as a signaling molecule, carrying the information about telomeric DNA damage to the cytoplasm, where several lines of DNA damage response may be triggered, or even communicated to other cells. As such, cytoTERRA, or the processes it is involved in, may in the future become a diagnostically important ALT hallmark or even a therapeutic target, although the concrete applications are difficult to predict. Telomeres are viewed as an important target in cancer biology, as their successful elongation in every cell division is an acquired characteristic important for the survival of cancer cells. Besides its possible direct outcomes, the results of the cytoTERRA project thus also add to a complicated picture, where uncountable pieces of knowledge contribute to the final puzzle that is cancer molecular biology.
The results we have acquired on cytoTERRA add to the emerging picture in the field of telomere biology that TERRA, beyond its roles at chromosome ends and in the nucleus, may serve as a signaling molecule, carrying the information about telomeric DNA damage to the cytoplasm, where several lines of DNA damage response may be triggered, or even communicated to other cells. As such, cytoTERRA, or the processes it is involved in, may in the future become a diagnostically important ALT hallmark or even a therapeutic target, although the concrete applications are difficult to predict. Telomeres are viewed as an important target in cancer biology, as their successful elongation in every cell division is an acquired characteristic important for the survival of cancer cells. Besides its possible direct outcomes, the results of the cytoTERRA project thus also add to a complicated picture, where uncountable pieces of knowledge contribute to the final puzzle that is cancer molecular biology.