Cancer cell niche factors secreted from cancer-associated fibroblast by loss of H3K27me3

Abstract

ObjectiveCancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells.DesignTwelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database.ResultsCAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal–epithelial interactions, such as WNT5A, GREM1, NOG and IGF2. Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration.ConclusionsH3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.

Wnt5a Signaling in Gastric Cancer

“…For instance, cancer-associated myofibroblasts (CAMs, also known as cancer-associated fibroblasts, or CAFs) from GC consistently displayed increased expression of Wnt5a, compared to adjacent tissue myofibroblasts (ATMs) . More recently, a study comparing the methylation and trimethylation (H3K23me3) patterns between CAFs and non-CAFs also identified WNT5A as a target for H3K23me3 predominantly in CAFs and corroborated that CAFs secreted more WNT5A than GC cell lines (Maeda et al, 2019). More importantly, this report showed that, in histological samples, WNT5A had higher expression in fibroblasts (which were identified by α-SMA staining), compared to cancer cells (Maeda et al, 2019).…”

Stroma secreted IL6 selects for “stem-like” population and alters pancreatic tumor microenvironment by reprogramming metabolic pathways

“…During tumor progression, this microenvironment develops anatomically distinct "niches", leading to enrichment of a small population of "stem-like" cells that have a distinct survival advantage over the bulk of the tumor cells. This population contributes to the aggressive biology of the disease [2][3][4] . Our previous studies show that this aggressive population has increased selfrenewal properties (contributing to tumor recurrence), increased invasiveness, and ability to evade adverse chemotherapeutic assault on the tumor and is represented by the expression of CD133 on their surface 5,6 .…”

Low-dose DNA demethylating therapy induces reprogramming of diverse cancer-related pathways at the single-cell level

“…In addition, enhancement of antigenicity of tumor cells by activation of endogenous retroviruses [ 18 , 19 ] was found to be an important mode of action. Recently, in addition to the effect on tumor cells, that on tumor cell niche, including cancer-associated fibroblasts and myeloid-derived suppressor cells (MDSCs) has been suggested also to be involved [ 20 – 22 ].…”