Gastric cancer CAFs maintain SASP through epigenetic histone modification and enhance peritoneal metastasis

Secreted factors from cancer associated fibroblast (CAFs) showing senescence-associated secretory phenotype (SASP) is likely to be implicated in cancer progression, but the precise mechanism is not fully understood. Here we showed that the growth ability of CAFs activated NFkB signaling decreased and their expression of senescent markers increased. The comprehensive genomic analysis revealed that these CAFs were highly enriched the senescent and SASP related genes. We also revealed the depletion of the H3K27me3 mark by inflammation-driven EZH2 downregulation leads to maintenance of SASP. Moreover, we found that senescent CAFs derived condition medium (CM) significantly increased the growth ability of GC cells and the peritoneal tumor through JAK/ STAT3 signaling. And, also JAK inhibitor significantly blocks the GC cell viability enhanced by senescent CAFs and the peritoneal tumor formation. These findings suggest that SASP factors maintain through histone demethylation in senescent CAFs and enhance peritoneal metastasis of GC cells.