| Summary: | Data now indicates that in addition to genetic alterations/mutations, human cancer cells exhibit important changes in their epigenome. In the context of this review, we define the epigenome as the chemical compounds and/or proteins that can interact with nuclear DNA to direct the specific and localized activation or silencing of genes to control the production of cellular proteins (directly or indirectly) in a given cell. Our ever-growing knowledge of how the epigenome can affect cellular processes has largely changed our view of cancer being a solely genetic disease. Nowadays, cancer is largely defined and characterized by the dynamic changes in both the genome and epigenome, which function together and contribute concomitantly to cancer initiation and progression. Since epigenetic modifications are crucial processes involved in controlling cellular identity and lineage fate, perturbations in this layer of gene regulation can contribute to the acquisition of new cellular characteristics different than those that were “initially” intended. For example, aberrant epigenetic alterations may transform normal non-cancer cells into cancer stem cells (CSCs), endowing them with the loss of differentiation and the acquisition of stem-like characteristics. In this review, we will focus our discussion on CSCs in the context of pancreatic ductal adenocarcinoma (PDAC). We will discuss how different epigenetic modifications create a landscape that can impact CSC identity and the way this small sub-population of cells contributes to tumor initiation, progression, and resistance to therapy. Moreover, we will highlight the latest discoveries in epigenetic-based therapies as a means of targeting CSCs.
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