Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination

• Main Authors: Tadahito Yasuda, Mayu Koiwa, Atsuko Yonemura, Keisuke Miyake, Ryusho Kariya, Sho Kubota, Takako Yokomizo-Nakano, Noriko Yasuda-Yoshihara, Tomoyuki Uchihara, Rumi Itoyama, Luke Bu, Lingfeng Fu, Kota Arima, Daisuke Izumi, Shiro Iwagami, Kojiro Eto, Masaaki Iwatsuki, Yoshifumi Baba, Naoya Yoshida, Hiroto Ohguchi, Seiji Okada, Keisuke Matsusaki, Goro Sashida, Akiko Takahashi, Patrick Tan, Hideo Baba, Takatsugu Ishimoto
• Format: Article
• Language: English
• Published: Elsevier 2021-02-01
• Series: Cell Reports
• Subjects: cancer-associated fibroblasts; senescence-associated secretory phenotype; EZH2; gastric cancer; peritoneal dissemination; H3K27me3 marks
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124721000929

Summary: 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.