Molecular Oncology Programme

Telomeres and Telomerase Group

Group Leader:  María A. Blasco
Research highlights
The PI3K/AKT pathway modulates telomere protection

We have described a role for PI3K/AKT in the regulation of TRF1, an essential component of the shelterin complex. Small molecule inhibitors of PI3K and AKT significantly reduce TRF1 telomeric foci and lead to increased telomeric DNA damage and fragility. We identified PI3Kα as the PI3K isoform responsible for this TRF1 inhibition. We found TRF1 is phosphorylated at different residues by AKT and that these modifications regulate TRF1 protein stability and TRF1 in vitro binding to telomeric DNA (FIGURE 1), and that they are important for in vivo TRF1 telomere location and cell viability. Patient-derived xenograft (PDX) breast cancer mouse models that responded effectively to a PI3Kα-specific inhibitor showed decreased TRF1 levels and increased telomeric DNA damage. Our discovery that the telomeric protein TRF1 is regulated by the PI3K signalling pathway not only functionally connects two of the hallmarks of cancer and ageing, but also pinpoints PI3K and AKT as novel targets for telomere-based therapies in cancer and age-related diseases.

Targeting telomeres as a therapeutic strategy for Glioblastoma Multiforme (GBM)

Glioblastoma multiforme is a deadly and common brain tumour. Its poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Disruption of telomere maintenance is among the most frequent alterations found in human glioblastoma, but no previous studies had validated telomeres as a good target to arrest GBM growth. TRF1 is a shelterin protein essential for both telomere protection and adult and pluripotent stem cells. We demonstrated that disrupting telomere capping through direct inhibition of TRF1 is a promising strategy for the treatment of GBM. We showed that inhibition of TRF1 blocks GBM in both mouse and human models (FIGURE 2). We also established the striking effectiveness of TRF1 inhibition in impairing the growth of glioma stem cells. Our results have a potential impact in cancer treatment as current GBM therapies are unable to kill these cells and patients die because of the strong recurrence of the tumours.

TRF1-based gene therapy rescues reduced TRF1 levels with ageing and prolongs mouse health span

TRF1 deficiency in the context of different mouse tissues leads to loss of tissue homeostasis due to impaired stem cell function. We have now shown that TRF1 levels decrease during organismal ageing, both in mice and in humans. We also showed that increasing TRF1 expression in both adult and old mice using gene therapy can delay age-associated pathologies. We used the non-integrative adeno-associated serotype 9 vector (AAV9), which allows for moderate and transient TRF1 overexpression. AAV9-TRF1 gene therapy prevented age-related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anaemia. We also found a lower abundance of short telomeres and of telomere-associated DNA damage in some tissues. Rescuing naturally decreased TRF1 levels during mouse ageing results in an improved mouse health span.

Common telomere changes during in vivo reprogramming and early stages of tumourigenesis

We studied whether tissue dedifferentiation induced by in vivo reprogramming involves changes at telomeres. In the reprogrammed areas, we found telomerase-dependent telomere elongation and telomere length-independent highly upregulated expression of TRF1. TRF1 inhibition reduced in vivo reprogramming efficiency. We extended the finding of TRF1 upregulation to pathological tissue dedifferentiation associated with neoplasias, specifically, to pancreatic acinarto-ductal metaplasia, a K-Ras driven process that involves transdifferentiation of adult acinar cells into ductal-like cellsOur findings place telomeres as important players in cellularplasticity both during in vivo reprogramming and in pathologicalconditions associated with increased plasticity, such as cancer.