Recent genetic advances have characterized the genomic landscape of osteosarcoma, including marked inter-tumoral/intrinsic heterogeneity and rare recurrent driver mutations.5 Preclinical studies revealed biological pathways implicated in tumorigenesis and therapy resistance, such as NF-kB, PI3K/mTOR, and WNT/β-catenin.6–9 However, in preclinical studies, cell culture of primary osteosarcoma cells or cell lines undergo extensive genetic changes and lose their phenotypic heterogeneity; thus, the conclusions from studies made with these cells are different from those of the primary tumors. This evidence concerns the gene NFKB1 and osteosarcoma.