Cholesterol-metabolic tumor-associated macrophages regulate tumor budding-like cell subpopulation to promote chordoma stemness via BACH1/ANGPTL4/SDC4 axis

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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.
Funding Information
  • National Natural Science Foundation of China (W2523095)
  • National Natural Science Foundation of China (82003802)
  • National Natural Science Foundation of China (82473965)
  • National Natural Science Foundation of China (82404690)
  • National Natural Science Foundation of China (82002364)
  • China Scholarship Council (202106370071)
  • China Postdoctoral Science Foundation (2025M782004)
  • Excellent & Innovative Talent Program, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (082550320)
  • Hubei Province High-Level Postdoctoral Talent Introduction Program (2005HBBHJD018)
  • Natural Science Foundation of Hunan Province (2019JJ50542)
  • Natural Science Foundation of Hunan Province (2023JJ50156)
  • Natural Science Foundation of Hunan Province (2023JJ40596)
  • Natural Science Foundation of Hunan Province (2023JJ40587)
  • Natural Science Foundation of Hunan Province (2021JJ40509)
  • Hunan Provincial Natural Science Foundation for Excellent Youth Scholars (2023JJ20035)
  • science and technology innovation Program of Hunan Province (2023RC3172)
  • Clinical Research 4310 Program of the First Affiliated Hospital of The University of South China (20224310NHYCG04)
  • Project for Clinical Research of Hunan Provincial Health Commission (20201978)
  • Project for Clinical Research of Hunan Provincial Health Commission (20201962)
  • Project for Clinical Research of Hunan Provincial Health Commission (20201956)
  • Research Foundation of Education Bureau of Hunan Province (22B0441)
  • Medical-Engineering Interdisciplinary Research Program of the First Affiliated Hospital, University of South China (IRP-M&E-2025-06)
  • Henan Province Science and Technology Research (252102311060)
  • Xiaohe Technology Talent Project of Hengyang city

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