| Autor: |
Asmita Thapa, Simone Landfredini, Andrew Blake, Stephanie Jones, Daniel S.T. Hughes, Clare Verrill, Adam Burns, Robert D. Goldin, Michael Eyres, Zahir Soonawalla, Anna Schuh, Eric O'Neill, Christine Blancher, Aswin George Abraham, Ahmad Sabbagh, Michael Silva, Tim Maughan, Frances Willenbrock, Aline Hubert, S. M. Hughes, Somnath Mukherjee, Zenobia D’Costa, Dimitris Vavoulis |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
Background and AimsPancreatic ductal adenocarcinoma (PDAC) is characterised by advanced disease stage at presentation, aggressive disease biology and resistance to therapy resulting in extremely poor five-year survival MethodsGenome-wide epigenetic mapping of DNA modifications 5-hydroxymethylcytosine (5mc) and 5-hydroxymethylcytosine (5hmc) using oxidative bisulphite sequencing (oxBS). Bioinformatics using iCluster and mutational profiling to identify overlap with transcriptional signatures in FFPE from resected patients and confirmation in vivo.ResultsWe find that more aggressive squamous-like PDAC subtypes result from epigenetic inactivation of loci including GATA6 that promote differentiated classical-pancreatic subtypes. We show that squamous-like PDAC transcriptional subtypes are associated with greater loss of 5hmc due to reduced expression of the 5mc-hydroxylase TET2. Furthermore, we find that SMAD4 directly supports TET2 levels in the pancreas and classical-pancreatic tumors and loss of SMAD4 expression is associated reduced 5hmc, GATA6 and squamous-like tumors. Importantly, enhancing TET2 stability using Metformin and VitaminC/ascorbic acid (AA) restores 5hmc and GATA6 levels, reverting squamous-like tumor phenotypes and WNT-dependence in vitro and in vivo.ConclusionsWe identify epigenetic deregulation of pancreatic differentiation as an underpinning event behind the emergence of transcriptomic subtypes in PDAC. Our data shows that restoring epigenetic control increases biomarkers of classical-pancreatic tumors and raises the possibility that combination of Vitamin C and Metformin may prolong survival in patients with squamous-like pancreatic cancer. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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