AccScience Publishing / IJB / Online First / DOI: 10.36922/IJB026040031
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RESEARCH ARTICLE

A vascularized 3D-bioprinted model of the osteosarcoma microenvironment reveals a proliferation-to-invasion switch that confers chemoresistance

Guang Tang1,2 ,  Zhongte Peng3 ,  Ying Zhao4 ,  Xin Chen4 ,  Shuai Huang5* ,  Guangfu Chen6* ,  Wei Guo4*
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1 Department of Orthopedics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
2 Department of Spinal Surgery, the Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, China
3 Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
4 Department of Orthopedic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
5 Department of Orthopaedic Surgery, The First People’s Hospital of Foshan, School of Medicine, Southern University of Science and Technology, Foshan, Guangdong, China
6 Department of Spinal Surgery, Foshan Fosun Chancheng Hospital, Foshan, Guangdong, China
IJB, 026040031 https://doi.org/10.36922/IJB026040031
Received: 25 January 2026 | Revised: 31 March 2026 | Accepted: 7 April 2026 | Published online: 24 April 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

The tumor microenvironment (TME) is a major driver of osteosarcoma progression, metastasis, and therapeutic resistance, yet conventional models fail to effectively recapitulate the multicellular interactions and biomechanical cues of the bone niche. In this study, we developed a vascularized 3D-bioprinted osteosarcoma model using a biomimetic hydrogel composed of decellularized extracellular matrix, chondroitin sulfate, and hydroxyapatite. U2OS osteosarcoma cells, human mesenchymal stem cells (HMSCs), and human umbilical vein endothelial cells were co-cultured within the printed constructs. Confocal imaging, RNA sequencing, xenograft validation, and integration with clinical single-cell RNA-sequencing data were used to define TME-driven changes in tumor behavior. The engineered TME induced a proliferation-to-invasion switch characterized by G0/G1 arrest, reduced proliferation activity, and enhanced invasiveness, angiogenic potential, and extracellular-matrix remodeling. Transcriptomic profiling showed downregulation of cell-cycle programs, including E2F and MYC targets, together with activation of TGF-β signaling, epithelial–mesenchymal transition (EMT), and hypoxia-related pathways. Mechanistically, HMSCs were identified as key regulatory cells that promoted migratory programs in tumor cells, partly through CXCL chemokine signaling engaging CXCR2. The TME-induced state also conferred robust chemoresistance to paclitaxel, associated with cell-cycle quiescence and pro-survival signaling, such as NF-κB activation. Critically, the transcriptional signature of these quiescent-invasive cells closely mirrored that of a clinically observed osteosarcoma subpopulation with low proliferation and high EMT activity. This high-fidelity vascularized 3D-bioprinted model recapitulates major TME-dependent features of osteosarcoma and provides a biologically relevant platform for studying tumor plasticity and evaluating therapies targeting microenvironment-driven treatment resistance.

Graphical abstract
Keywords
Osteosarcoma
Tumor microenvironment
3D bioprinting
Chemoresistance
Mesenchymal stem cells
Phenotypic switching
Funding
This work was supported by the Natural Science Foundation of Guangdong Province (Grant No. 2021A1515010447 to Wei Guo).
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing
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