Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination
Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination
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DOI：
10.1016/j.celrep.2021.108779
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发表时间：
2021-02-23
期刊：
影响因子：
8.8
通讯作者：
Ishimoto, Takatsugu
中科院分区：
文献类型：
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作者：
Yasuda, Tadahito;Koiwa, Mayu;Ishimoto, Takatsugu
在肿瘤微环境中，衰老的非恶性细胞，包括癌症相关成纤维细胞（CAF），在应激条件下表现出分泌特征;这种衰老相关分泌表型（SASP）导致癌症进展和化疗耐药性。然而，衰老CAFs在转移性病变中的作用以及炎症相关SASP诱导的分子机制尚不清楚。我们发现，促炎性的精氨酸驱动的EZH 2下调通过使CAFs中的H3 K27 me 3标记去甲基化来维持SASP，并通过JAK/STAT 3信号传导在小鼠模型中增强胃癌（GC）的腹膜肿瘤形成。JAK/STAT 3抑制剂阻断由衰老CAF和腹膜肿瘤形成诱导的GC细胞活力的增加。单细胞流式细胞术显示胃癌患者腹水中存在成纤维细胞，并且成纤维细胞群体显示高水平的p16表达和SASP因子。这些发现提供了深入了解炎症相关的SASP维护组蛋白修饰和衰老的CAFs在GC腹膜传播的作用。
In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this senescence-associated secretory phenotype (SASP) leads to cancer progression and chemoresistance. However, the role of senescent CAFs in metastatic lesions and the molecular mechanism of inflammation-related SASP induction are not well understood. We show that pro-inflammatory cytokine-driven EZH2 downregulation maintains the SASP by demethylating H3K27me3 marks in CAFs and enhances peritoneal tumor formation of gastric cancer (GC) through JAK/STAT3 signaling in a mouse model. A JAK/STAT3 inhibitor blocks the increase in GC cell viability induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry revealed that fibroblasts exist in the ascites of GC patients with peritoneal dissemination, and the fibroblast population shows p16 expression and SASP factors at high levels. These findings provide insights into the inflammation-related SASP maintenance by histone modification and the role of senescent CAFs in GC peritoneal dissemination.