Aggressive PDACs Show Hypomethylation of Repetitive Elements and the Execution of an Intrinsic IFN Program Linked to a Ductal Cell of Origin

Abstract

2-1). The collection and processing of the specimens via PancoBank was supported by Heidelberger 48 Stiftung Chirurgie. I.R. is a recipient of an Odysseus I fellowship of the Fund for Scientific Research 49 Flanders (FWO). E.E. was a recipient of an EMBO long-term fellowship (ALTF 344-2013).

Epigenetic Alterations in Pancreatic Cancer Metastasis

“…Because the IFN pathway is involved in anti-viral defense and activated stellate cells are involved in ECM remodeling, this pathway may be activating and reprogramming stellate cells to produce a pro-inflammatory stroma that facilitates tumor growth. Hypermethylation of homeobox genes, which encode key transcription factors of embryonic development, was also commonly detected in several PDA methylome studies [50,58,64,65]. This provides additional evidence that PDA tumors reactivate developmental pathways via epigenetic mechanisms to promote metastatic characteristics.…”

“…Interestingly, Nones et al also observed that stellate cell activation genes were often hypomethylated and therefore, likely downregulated in PDA [63]. In support of this, Espinet et al discovered that stellate cells exposed to conditioned media derived from high-interferon (IFN) signature patient tissues showed an increased stellate cell growth in vitro and tumor formation in vivo [64]. Because the IFN pathway is involved in anti-viral defense and activated stellate cells are involved in ECM remodeling, this pathway may be activating and reprogramming stellate cells to produce a pro-inflammatory stroma that facilitates tumor growth.…”

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

“…DNA methylation at CpG dinucleotides is a mechanism of cell-type specific gene regulation inherited in a continuous manner throughout development, hence it is a robust marker of cell identity 50 . Methylation patterns are now considered as a robust method to identify tumor cell-of-origins across tissues 51 , and in different cancer types 47,[52][53][54][55] . In addition, they have been used for characterization of subgroups within a tumor entity, for example in central nervous system tumors 56 , breast cancer 53 , ovarian cancer 57 as well as tissue origin of cell-free DNA (cfDNA) in disease 48 .…”

Epigenetic Alterations in Pancreatic Cancer Metastasis

“…Interestingly, Nones et al also observed that stellate cell activation genes were often hypomethylated and therefore, likely downregulated in PDA [20]. In support of this, Espinet et al discovered that stellate cells exposed to conditioned media derived from high-interferon (IFN) signature patient tissues showed an increased stellate cell growth in vitro and tumor formation in vivo [66]. Because the IFN pathway is involved in anti-viral defense and activated stellate cells are involved in ECM remodeling, this pathway may be activating and reprogramming stellate cells to produce a pro-inflammatory stroma that facilitates tumor growth.…”