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Palestra Colin Goding, University of Oxford (Inglaterra) - 05/04 das 11h às 13h

Cadastrado em 31/03/2016

Data: 05/04 das 11h às 13h

Local: Anfiteatro Verde do bloco 13A (FCF-USP)

Title: "Phenotype-switching and the molecular drivers of cancer progression: lessons from melanoma"

The interface between signal transduction pathways and transcription regulation acts to coordinate the programme of gene expression underlying the genesis of specific cell lineages and cellular proliferation and differentiation during development. Deregulation of transcription is a key factor in cancer. Our laboratory is interested in determining how a precise programme of transcription regulation is achieved, particularly in the transition between normal and cancer stem cells and their proliferating progeny, and the parallels with normal stem cell populations.

Over recent years we have made use of melanocytes and melanoma as a model system.

Melanocytes offer an interesting developmental system as mutations affecting the lineage result in an obvious coat colour phenotype, yet do not affect the viability of the animal. Moreover, melanoma, originating in the skin, offers a unique opportunity to examine a cancer at all stages of its development from benign naevi/moles to highly aggressive metastatic tumours.

We have recently proposed a new model for melanoma metastasis that reflects a dynamic and reversible epigenetic mechanism rather than irreversible genetic lesions, and have identified the transcription factor Mitf as a master regulator of melanoma proliferation, differentiation and invasiveness. We are currently analysing how Mitf integrates a wide range of signals to give a variable biological output and how this relates to melanoma stem cells that are proposed to provide a therapeutically resistant sub-population of cancer cells. Our most recent work has shown that it is possible to re-tool existing drugs to sensitise drug-resistant cells to novel therapies. We have also highlighted how post-translational modifications of transcription factors, especially MITF, lead to the establishment of specific melanoma subpopulations, and have identified MITF as a crucial link between cell stress and metabolism.

Our work is also uncovering a novel link between protein translation and transcription that is critical in generating invasive melanoma cells.

We have also shown the potential of pro-senescence therapy for this disease based on inhibition of the T-box transcription factors Tbx2 and Tbx3. Understanding how these factors inhibit senescence and how we can inhibit their function in melanoma is also a key aim and we are currently working towards developing pro-senescence drugs.

Finally our mechanistic studies on gene regulation have revealed a novel class of transcription factor we term 'promoter education factors' that act in a temporally distinct fashion from classical transcription activators to bring about the correct kinetics of gene expression in response to extracellular signals. We are currently exploring how such factors may contribute to priming stem cells for activation.