The estrogen response in fibroblasts promotes ovarian metastases of gastric cancer
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<sup>+</sup> GC cells. Collectively, our findings reveal that ER<sup>+</sup> 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.
Authors
- Fan Bai (ORCID: https://orcid.org/0000-0001-6119-8936)
- Shengjie Zhang (ORCID: https://orcid.org/0000-0001-6988-2791)
- Jiahui Chen (ORCID: https://orcid.org/0000-0001-9738-6605)
- Haohong Liang
- Qing Wei (ORCID: https://orcid.org/0000-0002-9007-5473)
- Yian Du (ORCID: https://orcid.org/0000-0002-8250-1209)
- Simeng Hu (ORCID: https://orcid.org/0000-0003-1212-7204)
- Zhiyuan Xu (ORCID: https://orcid.org/0000-0002-7257-6856)
- Can Hu (ORCID: https://orcid.org/0000-0002-8687-8310)
- Dan Su (ORCID: https://orcid.org/0000-0002-8423-1994)
- Pengfei Yu (ORCID: https://orcid.org/0009-0001-4331-5403)
- Litao Yang
- Yuan Li (ORCID: https://orcid.org/0000-0002-6245-9437)
- Xiangdong Cheng (ORCID: https://orcid.org/0000-0003-1470-2831)
- Ziyu Li (ORCID: https://orcid.org/0000-0001-9192-8178)
- Yanqiang Zhang (ORCID: https://orcid.org/0000-0002-9118-9800)
- Jingli Xu
Institutions
- Army Medical University (CN)
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- Zhejiang Cancer Hospital (CN)
- Xinqiao Hospital (CN)
- Cancer Hospital of Chinese Academy of Medical Sciences (CN)
- Center for Life Sciences (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-30
- DOI
- https://doi.org/10.1038/s41467-024-52615-9
- Citations
- 23
- Primary Topic
- Ovarian cancer diagnosis and treatment
- Type
- article
- Field-Weighted Citation Impact
- 12.35
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Beijing Municipality
- National Key Research and Development Program of China
- Medical Science and Technology Project of Zhejiang Province
- Science and Technology Program of Zhejiang Province