SYSTUMS · Systems biology approaches to novel Tumour Suppressors

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.