Cholesterol-metabolic tumor-associated macrophages regulate tumor budding-like cell subpopulation to promote chordoma stemness via BACH1/ANGPTL4/SDC4 axis
Year: 2025
Type: article
Abstract: BACKGROUND: Tumor budding (TB) is a well-established prognostic indicator in various epithelial malignancies. Chordoma, although a rare mesenchymal tumor, paradoxically exhibits prominent epithelial-like characteristics, as demonstrated in previous studies. In particular, it remains unclear whether TB-like (TBL) structures are present in chordoma, as well as the molecular mechanisms driving their formation and their functional impact on tumor progression, representing a critical gap in current knowledge. METHODS: Tumor budding-like grades were defined and evaluated in tumor specimens from 481 chordoma patients across 4 large cohorts using hematoxylin-eosin and immunohistochemical staining. Multi-omics profiling, encompassing GeoMx digital spatial profiling, spatial transcriptomics, bulk RNA sequencing, single-cell RNA sequencing, single-cell ATAC sequencing, and multiplex quantitative immunofluorescence, was integrated to delineate TBL cell subpopulations (TBLCs) and their interactions with cholesterol-metabolic tumor-associated macrophages (CM-TAMs). Organoid models and in vitro/in vivo functional assays were employed for mechanistic investigation and validation. RESULTS: Tumor budding-like structures were prevalent in chordoma, and higher TBL grades were associated with unfavorable clinical outcomes and aggressive phenotypes. Mechanistically, BACH1 in CM-TAMs drove ANGPTL4 secretion, which targeted the SDC4 receptor on TBLCs, thereby enhancing stem-like properties, promoting cholesterol accumulation, and accelerating malignant progression. Pharmacological inhibition of cholesterol metabolism or disruption of the BACH1-ANGPTL4-SDC4 signaling axis markedly reduced tumor invasiveness in both preclinical models and chordoma organoids. CONCLUSIONS: BACH1-driven CM-TAMs activate TBLCs via the ANGPTL4-SDC4 signaling axis, promoting stemness and cholesterol accumulation, ultimately driving malignant progression in chordoma. These findings uncover a previously unrecognized tumor-immune-metabolic interaction and suggest potential therapeutic targets for this disease.
Source: Neuro-Oncology
Authors: Bo-Wen Zheng, Chao Xia, Wei Huang, Hua-Qing Niu, Bang-Min Luo, Shen-Quan Liang, Bo-Yv Zheng, Ling-Xiang Jiang, Peng-Fei Wu, Jing Li, Makoto Endo, Tao-Lan Zhang, Ming-Xiang Zou
Institutions: Peking University, Peking University People's Hospital, Wuhan Union Hospital, First Affiliated Hospital of University of South China, General Hospital of Central Theater Command, Huazhong University of Science and Technology, University of South China, Zhengzhou University, Second Affiliated Hospital of Zhengzhou University, Chenzhou First People's Hospital, Indiana University Indianapolis, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Guangzhou Women and Children Medical Center, Guangzhou Medical University, Central South University, Second Xiangya Hospital of Central South University, Xiangya Hospital Central South University, Kyushu University
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4417354712