Transcriptional control of phenotype in melanoma
<p>Melanoma is the most aggressive and deadly type of skin cancer, mainly as a consequence of its high metastatic capacity and refractoriness to treatment. Over recent years increasing evidence suggests that the intra-tumour microenvironment can drive cells to adopt invasive and drug-resist...
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| Format: | Thesis |
| Language: | English |
| Published: |
2019
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| Summary: | <p>Melanoma is the most aggressive and deadly type of skin cancer, mainly as a consequence of its high metastatic capacity and refractoriness to treatment. Over recent years increasing evidence suggests that the intra-tumour microenvironment can drive cells to adopt invasive and drug-resistant phenotypes that play a key role in disease progression. Understanding how phenotypic heterogeneity is generated, and the molecular mechanisms underpinning the acquisition of invasive or drug-resistant states is key to the development of more effective therapies. Current evidence suggests an important role for the micropththalmia-associated transcription factor MITF in the development of phenotypic heterogeneity in melanoma. Yet how MITF is regulated and how it controls melanoma biology remains poorly characterised.</p> <p>Here we show that activating transcription factor 4 (ATF4), whose expression is induced via a translational switch that occurs under microenvironment stresses frequently found in tumours such as nutrient deprivation or hypoxia, has the potential to directly supress MITF expression and also directly target a repertoire of well-characterised and novel MITF target genes. In addition, ATF4 also directly binds and has the potential to activate expression of novel target genes linked to invasiveness/metastasis or with a cytoprotective role. Our results therefore suggest that in response to a stressful intra-tumour microenvironment the induction of ATF4 provides a potentially reversible mechanism for the generation of phenotype heterogeneity in melanoma leading to the acquisition of metastatic and/or drugresistant capacities in specific subpopulations of cells.</p> |
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