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Updated: Jan 18, 2026
Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
Targeting Cell-Matrix Induced Chemoresistance With Regorafenib in a 3D Model of Osteosarcoma
Rameshwar R Rao1,2, Michelle S Huang3, Daiyao Zhang3
1Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, Washington, USA.
Abstract:
Over the past four decades, there has been little advancement in treatment strategies for osteosarcoma (OS), the predominant primary bone tumor in the pediatric patient population. Current therapy involves multiple rounds of chemotherapy and surgical resection, which are associated with significant morbidity and suboptimal survival rates. A key challenge in developing new treatments is the difficulty in replicating the OS tumor microenvironment, particularly cell interactions with the extracellular matrix (ECM). This study uses an in vitro model of OS to investigate the cell response to collagen (COL) type I, the primary component of the OS ECM. After 7 days of culture within three-dimensional COL hydrogels, OS cells displayed a more elongated cellular morphology and reduced sensitivity to the standard chemotherapy used for OS treatment compared to cells grown on two-dimensional substrates. To test whether this model could be used to study treatment strategies used for high-risk OS patients, we applied a metronomic regimen combining regorafenib, a multi-tyrosine kinase inhibitor, with front-line chemotherapy to overcome cell-matrix induced chemoresistance. We identified overexpression of the ATP-binding cassette transporter ABCG2, a drug efflux pump, as a potential mechanism of resistance in 3D culture. Regorafenib's inhibitory effect on ABCG2 suggests a mechanistic basis for its ability to restore chemosensitivity in 3D culture. Altogether, these findings highlight the importance of cell-matrix interactions in in vitro OS models, provide valuable insights into a matrix-induced mechanism of OS chemoresistance, and suggest an approach to its treatment.
Insights
Osteosarcoma (OS) cells in 3D collagen gels show reduced chemotherapy sensitivity due to cell-matrix interactions. Combining regorafenib with chemotherapy may overcome this resistance by inhibiting ABCG2 drug efflux pumps.
Area of Science:
- Oncology
- Biomaterials Science
- Pharmacology
Background:
- Osteosarcoma (OS) treatment has seen limited progress over 40 years.
- Current therapies (chemotherapy, surgery) have significant side effects and suboptimal outcomes.
- Replicating the OS tumor microenvironment, especially cell-extracellular matrix (ECM) interactions, is crucial for developing new treatments.
Purpose of the Study:
- To investigate osteosarcoma cell response to collagen (COL) type I within a 3D in vitro model.
- To explore matrix-induced chemoresistance in OS.
- To evaluate a combination therapy (regorafenib + chemotherapy) to overcome chemoresistance in 3D OS models.
Main Methods:
- Culturing OS cells in 3D collagen type I hydrogels for 7 days.
- Comparing OS cell morphology and chemotherapy sensitivity in 3D versus 2D cultures.
- Applying a metronomic regimen of regorafenib and front-line chemotherapy to 3D OS cultures.
- Investigating the role of ATP-binding cassette transporter ABCG2 in chemoresistance.
Main Results:
- OS cells in 3D COL hydrogels exhibited altered morphology and reduced sensitivity to standard chemotherapy compared to 2D cultures.
- Overexpression of ABCG2, a drug efflux pump, was identified as a potential mechanism for 3D-induced chemoresistance.
- The combination therapy with regorafenib restored chemosensitivity in 3D OS cultures.
- Regorafenib demonstrated an inhibitory effect on ABCG2, suggesting a mechanism for overcoming chemoresistance.
Conclusions:
- Cell-matrix interactions significantly influence OS behavior and chemoresistance in vitro.
- A 3D OS model using collagen hydrogels effectively mimics aspects of the tumor microenvironment.
- The study identifies a matrix-induced chemoresistance mechanism involving ABCG2.
- Combination therapy with regorafenib shows promise for treating high-risk OS by restoring chemosensitivity.
