Adaptive Fibrogenic Reprogramming of Osteosarcoma Stem Cells Promotes Metastatic Growth

It is well established that fibrotic remodeling of the tumor microenvironment favors tumorigenesis, but whether fibrosis underlies malignant progression in other ways is unclear. Here, we report that adaptive myofibroblastic reprogramming of osteosarcoma stem cells (OSCs) results in a critical advantage when establishing lung macro-metastases and spheroid growth but does not affect the growth of primary lesions or monolayer cultures. FGFR2 signaling in OSCs initiates fibrosis, whereas the resultant fibronectin (FN) auto-deposition sustains fibrogenic reprogramming and OSC growth, resembling the process employed by non-malignant myofibroblasts to cause tissue fibrosis. Furthermore, we provide evidence that nintedanib targets the pan FGFR-FN axis to disrupt lung metastasis without affecting the bone lesion growth of OSCs. Thus, myofibroblastic reprogramming of human OSCs in the lungs might represent a druggable trait for treating a deadly metastatic complication.