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Background & aimsPancreatic ductal adenocarcinoma (PDAC) is characterized by advanced disease stage at presentation, aggressive disease biology, and resistance to therapy, resulting in an extremely poor 5-year survival rate of <10%. PDAC is classified into transcriptional subtypes with distinct survival characteristics, although how these arise is not known. Epigenetic deregulation, rather than genetics, has been proposed to underpin progression, but exactly why is unclear and is hindered by the technical limitations of analyzing clinical samples.MethodsWe performed genome-wide epigenetic mapping of DNA modifications 5-methylcytosine and 5-hydroxymethylcytosine (5hmc) using oxidative bisulfite sequencing from formalin-embedded sections. We identified overlap with transcriptional signatures in formalin-fixed, paraffin-embedded tissue from resected patients, via bioinformatics using iCluster and mutational profiling and confirmed them in vivo.ResultsWe found that aggressive squamous-like PDAC subtypes result from epigenetic inactivation of loci, including GATA6, which promote differentiated classical pancreatic subtypes. We showed that squamous-like PDAC transcriptional subtypes are associated with greater loss of 5hmc due to reduced expression of the 5-methylcytosine hydroxylase TET2. Furthermore, we found that SMAD4 directly supports TET2 levels in classical pancreatic tumors, and loss of SMAD4 expression was associated with reduced 5hmc, GATA6, and squamous-like tumors. Importantly, enhancing TET2 stability using metformin and vitamin C/ascorbic acid restores 5hmc and GATA6 levels, reverting squamous-like tumor phenotypes and WNT-dependence in vitro and in vivo.ConclusionsWe identified epigenetic deregulation of pancreatic differentiation as an underpinning event behind the emergence of transcriptomic subtypes in PDAC. Our data showed that restoring epigenetic control increases biomarkers of classical pancreatic tumors that are associated with improved therapeutic responses and survival.

Original publication

DOI

10.1053/j.gastro.2021.04.044

Type

Journal article

Journal

Gastroenterology

Publication Date

08/2021

Volume

161

Pages

653 - 668.e16

Addresses

Department of Oncology, University of Oxford, Oxford, UK.

Keywords

Cell Line, Tumor, Animals, Mice, Transgenic, Humans, Mice, Nude, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Metformin, Ascorbic Acid, 5-Methylcytosine, Dioxygenases, DNA-Binding Proteins, Antineoplastic Combined Chemotherapy Protocols, Retrospective Studies, Xenograft Model Antitumor Assays, Gene Expression Profiling, Cell Differentiation, DNA Methylation, Transcription, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, GATA6 Transcription Factor, Smad4 Protein, Epigenomics, Transcriptome, Wnt Signaling Pathway, Biomarkers, Tumor, Epigenome