Senescence and cancer
Cells have evolved to respond to damaging signals through certain so-called cell intrinsic checkpoint mechanisms. Depending on the duration of the signal and the extent of damage, cellular senescence or cell death may ensue. These cellular phenomena are of interest due to their close mechanistic association with prolonged oncogene activation and loss of tumour suppressor function, both cancer-inducing signals. Scientists on the EU-funded 'Systems biology approaches to novel tumour suppressors' (SYSTUMS) project exploited the link between senescence and cancer to identify tumour-driving genes. With a focus on lung cancer, they applied a cell-based senescence screen to search for putative new tumour suppressors. They found that one of the most frequently mutated genes in human lung cancers, the gene that encodes the EPHA3 receptor tyrosine kinase, is associated with cellular senescence. To further explore the function of this transmembrane receptor, researchers manipulated EPHA3-mediated signalling. Loss of EPHA3 function induced aberrant proliferation by eliciting key cellular senescence pathways, including activation of the p53 pathway. In lung cancer, EPHA3 function can be disrupted via point mutations in the receptor or loss of its genomic locus. Since EPHA receptors regulate cell positioning and migration in the tissue microenvironment, SYSTUMS scientists went on to investigate the in vivo function of EPHA3 using mouse models of cancer. Constitutive loss of EphA3 did not affect the outcome of mutant Kras- or p53 loss-driven lung cancer. Interestingly, EPHA3 is uniquely expressed in the embryonic lung distal mesenchyme, although no evidence for defective lung morphogenesis was found in embryos lacking EPHA3. Further experimentation will be required to unequivocally assess the role of EPHA3 during lung development and adult lung function. At the same time, this study indicates that more sophisticated tools such as conditional mouse models of EphA3 loss are needed to fully unravel its role in lung cancer development. Overall, the findings of the SYSTUMS study indicate a close association between senescence and cancer formation. Identifying the pathways and molecules for this transition may reveal cancer intervention strategies.
