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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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2019
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| _version_ | 1826313225061269504 |
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| author | Mosteo López, L |
| author2 | Goding, C |
| author_facet | Goding, C Mosteo López, L |
| author_sort | Mosteo López, L |
| collection | OXFORD |
| description | <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> |
| first_indexed | 2024-03-07T05:56:57Z |
| format | Thesis |
| id | oxford-uuid:ead8ce20-fcbc-4e20-873c-9dfccbd36e84 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:08:09Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:ead8ce20-fcbc-4e20-873c-9dfccbd36e842024-06-05T07:32:52ZTranscriptional control of phenotype in melanomaThesishttp://purl.org/coar/resource_type/c_db06uuid:ead8ce20-fcbc-4e20-873c-9dfccbd36e84EnglishORA Deposit2019Mosteo López, LGoding, C<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> |
| spellingShingle | Mosteo López, L Transcriptional control of phenotype in melanoma |
| title | Transcriptional control of phenotype in melanoma |
| title_full | Transcriptional control of phenotype in melanoma |
| title_fullStr | Transcriptional control of phenotype in melanoma |
| title_full_unstemmed | Transcriptional control of phenotype in melanoma |
| title_short | Transcriptional control of phenotype in melanoma |
| title_sort | transcriptional control of phenotype in melanoma |
| work_keys_str_mv | AT mosteolopezl transcriptionalcontrolofphenotypeinmelanoma |