Regulation of molecular subtypes of pancreatic cancer by TET2 and 5'hmC
<p>Genomic studies using mRNA datasets have uncovered two molecular subtypes within pancreatic ductal adenocarcinoma (PDAC) tumours with distinct gene programmes and clinical characteristics, raising the possibility of subtype specific therapeutic options. In each of these studies a similar ag...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2019
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| _version_ | 1817932678455885824 |
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| author | Eyres, MMD |
| author2 | O’Neill, E |
| author_facet | O’Neill, E Eyres, MMD |
| author_sort | Eyres, MMD |
| collection | OXFORD |
| description | <p>Genomic studies using mRNA datasets have uncovered two molecular subtypes within pancreatic ductal adenocarcinoma (PDAC) tumours with distinct gene programmes and clinical characteristics, raising the possibility
of subtype specific therapeutic options. In each of these studies a similar aggressive subtype was identified that was characterized by a loss of
endodermal differentiation markers such as GATA6 and PDX1, as well as
poorer patient survival, referred to collectively as squamous. Despite the
inherent heterogeneity in the molecular basis of PDAC, there is little genetic heterogeneity between different PDAC tumours, even when comparing
metastasis to primary tumours. Conversely, there is widespread epigenetic
reprogramming association with progression to more aggressive phenotypes,
suggesting that aggressive molecular subtypes are likely to be epigenetically
driven.</p>
<p>TET-mediated DNA Hydroxymethylation (5’hmC) is dynamically regulated during pancreatic differentiation, but it remains unknown what role
5’hmC during PDAC initiation and progression. In this work the role of
5’hmC during PDAC progression is explored. Loss of 5’hmC correlates with
squamous subtypes and decreased expression of GATA6 while re-expression
of TET2 increases GATA6 expression. Critically, TET2 can be effectively
targeted using Metformin and Vitamin C (Ascorbic Acid). When used in
combination, metformin and ascorbic acid can increase TET2 and GATA6
levels in vitro and in vivo. This suppresses Wnt pathway signalling and
causes cells to become less squamous in identity. Thus, the findings presented here suggest that aggressive molecular subtypes can be targeted therapeutically be restoring TET2 activity.</p> |
| first_indexed | 2024-03-06T20:42:03Z |
| format | Thesis |
| id | oxford-uuid:349cc4e0-b1f9-4464-af8c-e967d99244e0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:41:44Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:349cc4e0-b1f9-4464-af8c-e967d99244e02024-12-07T12:52:31ZRegulation of molecular subtypes of pancreatic cancer by TET2 and 5'hmCThesishttp://purl.org/coar/resource_type/c_db06uuid:349cc4e0-b1f9-4464-af8c-e967d99244e0OncologyEpigeneticsEnglishHyrax Deposit2019Eyres, MMDO’Neill, E<p>Genomic studies using mRNA datasets have uncovered two molecular subtypes within pancreatic ductal adenocarcinoma (PDAC) tumours with distinct gene programmes and clinical characteristics, raising the possibility of subtype specific therapeutic options. In each of these studies a similar aggressive subtype was identified that was characterized by a loss of endodermal differentiation markers such as GATA6 and PDX1, as well as poorer patient survival, referred to collectively as squamous. Despite the inherent heterogeneity in the molecular basis of PDAC, there is little genetic heterogeneity between different PDAC tumours, even when comparing metastasis to primary tumours. Conversely, there is widespread epigenetic reprogramming association with progression to more aggressive phenotypes, suggesting that aggressive molecular subtypes are likely to be epigenetically driven.</p> <p>TET-mediated DNA Hydroxymethylation (5’hmC) is dynamically regulated during pancreatic differentiation, but it remains unknown what role 5’hmC during PDAC initiation and progression. In this work the role of 5’hmC during PDAC progression is explored. Loss of 5’hmC correlates with squamous subtypes and decreased expression of GATA6 while re-expression of TET2 increases GATA6 expression. Critically, TET2 can be effectively targeted using Metformin and Vitamin C (Ascorbic Acid). When used in combination, metformin and ascorbic acid can increase TET2 and GATA6 levels in vitro and in vivo. This suppresses Wnt pathway signalling and causes cells to become less squamous in identity. Thus, the findings presented here suggest that aggressive molecular subtypes can be targeted therapeutically be restoring TET2 activity.</p> |
| spellingShingle | Oncology Epigenetics Eyres, MMD Regulation of molecular subtypes of pancreatic cancer by TET2 and 5'hmC |
| title | Regulation of molecular subtypes of pancreatic cancer by TET2 and 5'hmC |
| title_full | Regulation of molecular subtypes of pancreatic cancer by TET2 and 5'hmC |
| title_fullStr | Regulation of molecular subtypes of pancreatic cancer by TET2 and 5'hmC |
| title_full_unstemmed | Regulation of molecular subtypes of pancreatic cancer by TET2 and 5'hmC |
| title_short | Regulation of molecular subtypes of pancreatic cancer by TET2 and 5'hmC |
| title_sort | regulation of molecular subtypes of pancreatic cancer by tet2 and 5 hmc |
| topic | Oncology Epigenetics |
| work_keys_str_mv | AT eyresmmd regulationofmolecularsubtypesofpancreaticcancerbytet2and5hmc |