The estrogen response in fibroblasts promotes ovarian metastases of gastric cancer

Simeng Hu, Can Hu, Jingli Xu, Pengfei Yu, Li Yuan, Ziyu Li, Haohong Liang, Yanqiang Zhang, Jiahui Chen, Qing Wei, Shengjie Zhang, Litao Yang, Dan Su, Yian Du, Zhiyuan Xu (), Fan Bai () and Xiangdong Cheng ()
Additional contact information
Simeng Hu: Peking University
Can Hu: Chinese Academy of Sciences
Jingli Xu: Chinese Academy of Sciences
Pengfei Yu: Chinese Academy of Sciences
Li Yuan: Chinese Academy of Sciences
Ziyu Li: Peking University
Haohong Liang: Peking University
Yanqiang Zhang: Chinese Academy of Sciences
Jiahui Chen: Chinese Academy of Sciences
Qing Wei: Chinese Academy of Sciences
Shengjie Zhang: Chinese Academy of Sciences
Litao Yang: Chinese Academy of Sciences
Dan Su: Chinese Academy of Sciences
Yian Du: Chinese Academy of Sciences
Zhiyuan Xu: Chinese Academy of Sciences
Fan Bai: Peking University
Xiangdong Cheng: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Younger premenopausal women are more prone to developing ovarian metastases (OM) of gastric cancer (GC) than metastases of other organs; however, the molecular mechanisms remain unclear. Here we perform single-cell RNA sequencing on 45 tumor samples from 18 GC patients with OM. Interestingly, fibroblasts in OM of GC express high levels of estrogen receptor (ER) and midkine (MDK), interacting with tumor cells through activating ER-MDK-LRP1 (low-density lipoprotein receptor-related protein 1) signaling axis. Functional experiments demonstrate that estrogen stimulation induces MDK secretion by ovarian fibroblasts, and binding of MDK to LRP1 increases GC cell migration and invasion. Furthermore, in vivo, estrogen stimulation remarkably augments ovarian engraftment and metastasis of LRP1+ GC cells. Collectively, our findings reveal that ER+ ovarian fibroblasts secrete MDK under estrogen influence, driving OM of GC via the MDK-LRP1 axis. Our study holds the potential to catalyze innovative therapeutic strategies aimed at intercepting and managing OM in GC.

Date: 2024
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DOI: 10.1038/s41467-024-52615-9

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