A novel mechanism of cellular senescence
Described as the phenomenon of irreversible cell growth arrest, cellular senescence can be triggered by multiple mechanisms. Together, these mechanisms limit excessive or aberrant cellular proliferation, and so the state of senescence protects against the development of cancer. The primary goal of the EU-funded ''Pro-senescence' therapy in pediatric brain tumours' (SENESCENCE THERAPY) project was to investigate a novel type of cellular senescence. Researchers recently discovered a type of cellular senescence response to the loss of the tumour-suppressor phosphatase and tensin homologue (PTEN). Mutations of this gene are a step in the development of many cancers. Subtle reduction in PTEN levels promotes tumour initiation and progression. However, new studies have shown that complete inactivation of PTEN drives senescence even in the absence of hyper replication and a DNA damage response. Researchers named this novel senescence response PTEN-loss–induced cellular senescence (PICS). The researchers demonstrated that PICS depends on the functional activity of the mammalian target of rapamycin (mTOR)-mediated p53 translation. Therefore, loss of the tumour-suppressor p53 promotes senescence evasion, tumour invasion and cancer progression. In a prostate cancer xenograft model, pharmacological inhibition of PTEN drove senescence and tumour growth arrest in vivo. Medulloblastoma and neuroblastoma are two main intra- and extra-cranial paediatric tumours. Usually, these tumours are associated with alteration of the proto-oncogenes c-myc and n-myc. However, they retain a normal PTEN and p53 status. As such, they represent an ideal model system to test the efficacy of novel pro-senescence compounds either alone or in combination. The primary aim for the next step in this project is to demonstrate the efficacy of the novel PTEN inhibitors in this model system. Therefore, this project has the potential to provide additional therapeutic options for the cure of these frequent paediatric tumours.
