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

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.

癌症相关成纤维细胞（cancer associated fibroblast, CAFs）分泌的、呈现衰老相关分泌表型（senescence-associated secretory phenotype, SASP）的分泌因子可能参与癌症进展过程，但其精确调控机制尚未完全阐明。本研究证实，经NFκB信号通路活化的CAFs其增殖能力下降，且衰老标志物的表达水平显著升高；全基因组综合分析显示，此类CAFs显著富集衰老及SASP相关基因。本研究还揭示，炎症驱动的EZH2（enhancer of zeste homolog 2）下调会导致H3K27me3（histone H3 lysine 27 trimethylation）标记缺失，进而维持SASP表型。此外，本研究发现，衰老CAFs的条件培养基（condition medium, CM）可通过JAK/STAT3信号通路显著促进胃癌（gastric cancer, GC）细胞增殖与腹腔肿瘤形成，且JAK抑制剂可显著阻断衰老CAFs介导的胃癌细胞活力升高及腹腔肿瘤生成。上述研究结果表明，衰老CAFs通过组蛋白去甲基化维持SASP表型，并增强胃癌细胞的腹腔转移能力。