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

• Published in: Cell reports (Cambridge) Vol. 34; no. 8; p. 108779
• Main Authors: Yasuda, Tadahito, Koiwa, Mayu, Yonemura, Atsuko, Miyake, Keisuke, Kariya, Ryusho, Kubota, Sho, Yokomizo-Nakano, Takako, Yasuda-Yoshihara, Noriko, Uchihara, Tomoyuki, Itoyama, Rumi, Bu, Luke, Fu, Lingfeng, Arima, Kota, Izumi, Daisuke, Iwagami, Shiro, Eto, Kojiro, Iwatsuki, Masaaki, Baba, Yoshifumi, Yoshida, Naoya, Ohguchi, Hiroto, Okada, Seiji, Matsusaki, Keisuke, Sashida, Goro, Takahashi, Akiko, Tan, Patrick, Baba, Hideo, Ishimoto, Takatsugu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.02.2021; Elsevier
• Subjects: Aged; Animals; Antineoplastic Agents - pharmacology; cancer-associated fibroblasts; Cancer-Associated Fibroblasts - enzymology; Cancer-Associated Fibroblasts - pathology; Cell Line, Tumor; Cytokines - genetics; Cytokines - metabolism; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; EZH2; Female; gastric cancer; Gene Expression Regulation, Neoplastic; H3K27me3 marks; Humans; Inflammation Mediators - metabolism; JAK inhibitor; Janus Kinase Inhibitors - pharmacology; Janus Kinases - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; peritoneal dissemination; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - genetics; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - secondary; Pyridines - pharmacology; Senescence-Associated Secretory Phenotype; Signal Transduction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Tumor Microenvironment; Tyrphostins - pharmacology; Xenograft Model Antitumor Assays; cancer-associated fibroblasts; gastric cancer; peritoneal dissemination; H3K27me3 marks; JAK inhibitor; senescence-associated secretory phenotype; EZH2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108779

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. [Display omitted] •EZH2 downregulation leads to SASP maintenance through depletion of H3K27me3 marks•Senescent CAFs in ascites of GC patients with peritoneal dissemination exhibit SASP•Senescent CAFs enhance the peritoneal tumor formation through JAK/STAT3 signaling•A JAK inhibitor blocks peritoneal tumor formation driven by systemic inflammation Yasuda et al. show the fundamental mechanism by which inflammation-driven senescent CAFs enhance the peritoneal dissemination and the significance of targeting senescent CAFs as well as JAK/STAT3 signaling in GC cells. These findings provide a promising therapeutic approach for GC peritoneal dissemination driven by systemic inflammation.