Hypoxic Upregulation of IER2 Increases Paracrine GMFG Signaling of Endoplasmic Reticulum Stress-CAF to Promote Chordoma Progression via Targeting ITGB1.

Autor: Zhang TL; Department of Pharmacy, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China., Zheng BW; Department of Pharmacy, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China.; Musculoskeletal Tumor Center, Peking University People's Hospital, Peking University, Beijing, 100044, China., Xia C; Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China., Wu PF; Department of Genetics and Endocrinology, National Children's Medical Center for South Central Region, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510623, China., Zheng BY; Department of Orthopedics Surgery, General Hospital of the Central Theater Command, Wuhan, 430061, China., Jiang LX; Department of Radiation Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Li J; Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China., Lv GH; Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, China., Zhou H; Department of Radiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China., Huang W; The First Affiliated Hospital, Health Management Center, Hengyang Medical School, University of South China, Hengyang, 421001, China., Zou MX; Department of Spine Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Oct; Vol. 11 (40), pp. e2405421. Date of Electronic Publication: 2024 Aug 29.
DOI: 10.1002/advs.202405421
Abstrakt: Currently, the oncogenic mechanism of endoplasmic reticulum stress-CAF (ERS-CAF) subpopulation in chordoma remains unknown. Here, single-cell RNA sequencing, spatial transcriptomics, GeoMx Digital Spatial Profiler, data-independent acquisition proteomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence are used to unveil the precise molecular mechanism of how ERS-CAF affected chordoma progression. Results show that hypoxic microenvironment reprograms CAFs into ERS-CAF subtype. Mechanistically, this occurrs via hypoxia-mediated transcriptional upregulation of IER2. Overexpression of IER2 in CAFs promotes chordoma progression, which can be impeded by IER2 knockdown or use of ERS inhibitors. IER2 also induces expression of ERS-CAF marker genes and results in production of a pro-tumorigenic paracrine GMFG signaling, which exert its biological function via directly binding to ITGB1 on tumor cells. ITGB1 inhibition attenuates tumor malignant progression, which can be partially reversed by exogenous GMFG intervention. Further analyses reveal a positive correlation between ITGB1 high tumor cell counts and SPP1 + macrophage density, as well as the spatial proximity of these two cell types. Clinically, a significant correlation of high IER2/ITGB1 expression with tumor aggressive phenotype and poor patient survival is observed. Collectively, the findings suggest that ERS-CAF regulates SPP1 + macrophage to aggravate chordoma progression via the IER2/GMFG/ITGB1 axis, which may be targeted therapeutically in future.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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