SYSTUMS

Systems biology approaches to novel Tumour Suppressors

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 Obiettivo del progetto (Objective)

'Cells contain in-built checkpoint mechanisms to halt division when cells are somehow compromised in their ability to replicate properly, allowing time to repair or adjust the inflicted machinery. If the damage signal persists, cells eventually undergo irreversible cellular faiths, including cellular senescence or apoptosis. Of interest to cancer researchers, apoptosis and senescence upon prolonged oncogene activation or loss of tumor suppression is an emerging paradigm, and is even detected in early stage human tumors. I reasoned that a senescence screen should reveal novel cancer genes, and undertook a kinome siRNA screen employing a cell based morphology screen in diploid, untransformed epithelial cells. One of the candidate tumor suppressors thus identified was the EPHA3 receptor tyrosine kinase gene, which is found to be frequently mutated in human lung and colorectal cancers in several cancer genome sequencing efforts. However the details of how receptor mutation contributes to tumour formation remain unclear. We aim to further explore these research angles through studying molecular networks around and cell system responses to the manipulation of EphA3 receptor signalling. Considering the role of Eph receptors in cell shape and migration, it will be essential to study its putative tumour suppressive functions in a system resembling in vivo architecture. The integration of molecular, cell biological and epithelial cellular system approaches with genomic profiling will add to our understanding of this poorly studied cancer pathway. Furthermore, an understanding of checkpoint responses to cancer mutations, including EphA3 pathway alterations, may enable us to shift responses towards apoptosis or prevent checkpoint escape and reveal cancer prevention strategies.'

Introduzione (Teaser)

One of the hallmarks of cancer is uncontrollable cell proliferation. Identifying how cancer cells overcome growth restrictions to generate tumours represents a major challenge.

Descrizione progetto (Article)

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.