Characterising drivers of melanoma cell heterogeneity

Tumour cell heterogeneity is linked to tumour progression through the generation of divergent cellular behaviours such as proliferation, survival, invasion and therapy resistance.  Crucially, conventional and targeted therapies generally only target highly proliferative cells in tumours leading to initial tumour regression, however alternative sub-populations underpin the return of treatment refractory disease and facilitate metastatic spread.  Our laboratory is focused on understanding the regulatory drivers of cellular plasticity in melanoma to better understand progression and metastatic spread of this disease and to identify potential therapeutic vulnerabilities in these poorly targeted cell populations.  Central to our research agenda is to understand the phenotype switch facilitated by two transcription factors in melanoma cells, BRN2 and MITF, that drive predominantly invasive/metastatic or proliferative behaviours respectively.  Our work has identified additional down-stream drivers of melanoma invasion such as NFIB that is potentially a master regulator of metastatic behaviour with evidence emerging of a central role in metastasis in a range of other cancer types.

We hypothesise that a transcriptional axis between BRN2, NFIB and MITF drives phenotypic heterogeneity of melanoma tumour cells (and potentially other tumour types) that ultimately governs the propensity for cells within the tumour to metastasise.

We will use a range of molecular and cell biology techniques to manipulate melanoma cell gene expression to dissect the functional role of BRN2 and NFIB and their down-stream target pathways.

References

Approaches/skills and techniques

Experimental approaches in this project may include melanoma cell transfection, lentiviral production and transduction, proliferation and migration/invasion assays, cloning, real-time-PCR, western blot analysis, immunofluorescence and immunohistochemistry.