Epigenetic regulation of the tumor microenvironment: A leading force driving pancreatic cancer

Abstract

Dysregulation of the epigenomic landscape of tumor cells has been implicated in the pathogenesis of pancreatic cancer. However, these alterations are not only restricted to neoplastic cells. The behavior of other cell populations in the tumor stroma such as cancer-associated fibroblasts, immune cells, and others are mostly regulated by epigenetic pathways. Here, we present an overview of the main cellular and acellular components of the pancreatic cancer tumor microenvironment and discuss how the epigenetic mechanisms operate at different levels in the stroma to establish a differential gene expression to regulate distinct cellular phenotypes contributing to pancreatic tumorigenesis.

Keywords: Epigenetics; Gene expression; Pancreatic cancer; Stroma; Tumor microenvironment.

Fig. 1.. Epigenetic landscape of stromal cells in the pancreatic cancer tumor microenvironment.

A, the interactions inside the TME trigger the epigenetic reprogramming of fibroblasts into different phenotypes of carcinoma-associated fibroblasts (CAFs) such as antigen-presenting CAFs (apCAFs), myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and metabolic CAFs (meCAFs). Also, these populations could transdifferentiate from one CAF phenotype to another. B, The TME influences epigenetic reprogramming of immune cells supporting the immune-suppressive microenvironment in PC. Under the influence of cancer cells, the myeloid linage could give rise to dendritic cells, myeloid-derived suppressor cells (MDSCs), TAMs, and T cells showing features of cell exhaustion (Tex).

Fig. 2.. The pancreatic cancer tumor microenvironment structure and composition.

A, Tumor cells establish interactions with well-defined collagen structures associated with the tumor (TACS). These structures are oriented either in parallel (TACS-2) or perpendicular (TACS-3) with respect to the tumor cell groups. Different publications have shown a more aggressive behavior in PC tissues enriched in TACS-3 structures, explaining that these collagen fiber arrangements could facilitate the spreading of tumor cells, reaching the blood vessels. B, Inflammatory fibroblasts influence different populations in the TME. Via CXCL2 secretion, iCAFs are able to polarize macrophages into TAMs together with the inhibition of the effector function of T cells, giving place to the exhaustion process. Similarly, through the secretion of the cytokine SDF1, iCAFs can promote tumor cell migration. C, Myeloid-derived suppressor cells (MDSCs) shape the immunosuppressive profile of pancreatic cancer TME. These cells increase the production of reactive oxygen species (ROS) and modulate the expression of immune checkpoints (PD-L1/PD-1) promoting anergy in effector cells. MDSCs affect macrophage polarization via IL-10 secretion.

Fig. 3.. Epigenetic Mechanisms modifying the gene expression in CAFs.

The epigenetic mechanisms operating to determine cellular fate in CAFs could include methylation of specific promoters (eg, SOCS1) and chromatin remodeling including histone modifications (A). Also, the gene expression of specific genes such as CXCL cytokines is determined by the generation of chromatin loops called topologically associated domains (TADs) in which gene interactions take place (B). Areas of specific attachment and interaction between the chromatin and the nuclear lamina (LADs) are characterized by a close chromatin status and repression of gene expression (C). Epigenetics also include the activity of noncoding RNAs (eg, pri-miR-21, CircCu12, etc) in the nucleoplasm (B), cytoplasm (C), and through extracellular vesicles (EV) from and to the cell surface (D).