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

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.

Context Matters—Why We Need to Change From a One Size Fits all Approach to Made-to-Measure Therapies for Individual Patients With Pancreatic Cancer

“…Genomic instability can occur at both, the genetic and epigenetic level ( Putiri and Robertson, 2011 ) and it increases as the tumor progresses. Epigenetics refers to the control of gene expression without changing the DNA sequence, e.g., via chemical modifications like methylation of the DNA, that can be passed on in cell divisions ( Jones and Baylin, 2007 ; Akhavan-Niaki and Samadani, 2013 ; Ciernikova et al, 2020 ; Alonso-Curbelo et al, 2021 ). Epigenetic changes like gene silencing by promoter hypermethylation or gene overexpression by promoter hypomethylation were shown to impact cancer progression ( Jones and Baylin, 2007 ).…”

“…Epigenetic drugs were shown to reduce tumorigenicity in pre-clinical models and some are already used in clinical trials ( Hessmann et al, 2017 ; Ciernikova et al, 2020 ; Morel et al, 2020 ). However, so far, they are associated with limited efficacy and not successful as monotherapy.…”

Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma

“…The complex interaction between genomic, epigenomic, and signaling pathway alterations affect PDAC growth and progression [ 136 ]. It has been shown that the EMT leads to the malignant phenotype in PCSCs.…”

Clinical and Pre-Clinical Evidence of Carbonic Anhydrase IX in Pancreatic Cancer and Its High Expression in Pre-Cancerous Lesions

“…Epigenetic changes, which are strongly affected by hypoxia, are an important feature of cancer development and progression [126]. Hypoxia upregulates the expression of different DNA methylation and demethylation enzymes.…”

“…Cooperation between hypoxia stimuli and paracrine signaling from an inflammatory environment, an inherent feature of pancreatic tumors, induces EMT, stemness, and promotes the formation of circulating tumor cells [126]. High CAIX expression was detected in tumor-initiating cells (TICs) positive for pancreatic cancer stem cell markers EpCAM + /CD44 + /CD24 + , isolated from PDAC patient samples [29].…”