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Review
. 2020 Jun 8;21(11):4091.
doi: 10.3390/ijms21114091.

Epigenetic Landscape in Pancreatic Ductal Adenocarcinoma: On the Way to Overcoming Drug Resistance?

Sona Ciernikova  1 , Julie Earl  2 , María Laura García Bermejo  3 , Viola Stevurkova  1 , Alfredo Carrato  2 , Bozena Smolkova  4
Affiliations
Review

Epigenetic Landscape in Pancreatic Ductal Adenocarcinoma: On the Way to Overcoming Drug Resistance?

Sona Ciernikova et al. Int J Mol Sci. .

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies due to the rapid rate of metastasis and high resistance to currently applied cancer therapies. The complex mechanism underlying the development and progression of PDAC includes interactions between genomic, epigenomic, and signaling pathway alterations. In this review, we summarize the current research findings on the deregulation of epigenetic mechanisms in PDAC and the influence of the epigenome on the dynamics of the gene expression changes underlying epithelial-mesenchymal transition (EMT), which is responsible for the invasive phenotype of cancer cells and, therefore, their metastatic potential. More importantly, we provide an overview of the studies that uncover potentially actionable pathways. These studies provide a scientific basis to test epigenetic drug efficacy in synergy with other anticancer therapies in future clinical trials, in order to reverse acquired therapy resistance. Thus, epigenomics has the potential to generate relevant new knowledge of both a biological and clinical impact. Moreover, the potential, hurdles, and challenges of predictive biomarker discoveries will be discussed, with a special focus on the promise of liquid biopsies.

Keywords: drug resistance; epi-drugs; epigenetics; epithelial–mesenchymal transition; liquid biopsy; pancreatic ductal adenocarcinoma.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the writing of the manuscript.

Figures

Figure 1
Figure 1
Progression model of PDAC. The stepwise accumulation of morphologic, histopathologic, genetic, and epigenetic changes are accompanied by immune cell infiltration and a desmoplastic stromal reaction. Abbreviations: CAF, cancer-associated fibroblast; ECM, extracellular matrix; MDSC, myeloid-derived suppressor cell; PSC, pancreatic stellate cell; TAM, tumor-associated macrophage.
Figure 2
Figure 2
Main factors that influence PDAC progression. PDAC consists of a minority of malignant cells within a microenvironment composed of an extracellular matrix (ECM) and a plethora of hematopoietic cells. Pancreatic stellate cells activated from the quiescent state by intrinsic and extrinsic stimuli (e.g., mechanical injury or chronic inflammation) play a key role. Once activated, they secrete an abundant amount of ECM proteins composed of hyaluronan, laminin, fibronectin, and collagens. By secreting ECM proteins, cytokines, and chemokines, they actively recruit monocytes and CD4 regulatory T cells (Tregs). Hematopoietic cells are predominantly of the myeloid lineage, with both granulocytic and monocytic myeloid-derived suppressor cells (MDSCs), as well as tumor-associated macrophages (TAMs). All contribute to local immunosuppression. KRAS mutation is an early oncogenic event that drives the recruitment of B cells early in the development of PDAC, which can exert immunosuppressive effects. Therefore, T cells, both CD4+ and CD8+, are not primed against PDAC antigens and are not excluded from tumors. The paucity of blood vessels leads to high levels of hypoxia in the interior of the tumor. Paracrine interactions between inflammatory cells and hypoxia stimuli induce EMT, which promotes circulating tumor cell (CTC) formation and endows differentiated normal and cancer cells with stem cell properties. They are characterized by a high expression of drug efflux pumps including multi-drug resistance genes, protecting them from chemotherapeutic reagents thus increasing their metastatic potential.
Figure 3
Figure 3
Schematic presentation of cancer-associated epigenetic modification abnormalities, including a brief overview of epi-drugs used in preclinical studies and clinical trials for PDAC treatment. Gene-specific hypermethylation accompanied by global DNA hypomethylation, frequent mutation of epigenetic modifiers and histone proteins, as well as abnormal histone modification patterns are typical cancer-associated epigenetic changes. A large number of the first-, second- and third-generation inhibitors, targeting epigenetic modifications, were used in preclinical studies and clinical trials. Although epi-drug monotherapies were not successful, combination therapy targeting diverse chromatin regulators or a biomarker-directed approach that combines a new generation of epi-drugs with traditional approaches currently represent the most promising concept for PDAC.
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