Extracellular Matrix Degradation to Overcome Osteosarcoma Chemoresistance

The Rao Lab at Seattle Children's Research Institute developed a three-dimensional (3D) tissue-engineered model of osteosarcoma to investigate the effects of the extracellular matrix on malignant cell function. The study demonstrated that culturing osteosarcoma (OS) cells within a 3D collagen matrix induced unique cellular responses, altered morphology, enhanced tumorigenic behavior, and reduced chemosensitivity compared to cells cultured in 2D collagen or on standard tissue culture plastic. They identified overexpression of drug efflux pumps as a key mechanism of chemoresistance and further showed that a tyrosine kinase inhibitor could suppress drug efflux activity, thereby enhancing the efficacy of standard chemotherapeutic agents.While this earlier study examined the effects of a single collagen concentration on osteosarcoma phenotype, clinical solid tumors are characterized by altered extracellular microarchitecture, including increased matrix density and stiffness. These changes restrict drug transport and limit chemotherapy-induced cell death.Dr. Rao will present findings from engineered tumor models incorporating varying matrix densities and demonstrate how matrix density influences osteosarcoma function. This work was funded by the 2025 Outsmarting Osteosarcoma Young Investigator Hope Award.Dr. Rao is a Pediatric Hematologist Oncologist at the Seattle Children's Hospital and a Principal Investigator in the Ben Towne Center for Childhood Cancer and Blood Disorders Research at the Seattle Children's Research Institute. His lab harnesses biomaterials and tissue engineering technologies to design 3D models of osteosarcoma to understand how cell-matrix interactions lead to chemoresistance.