Using a TCF/Lef reporter assay (TOPFLASH), we showed that three LGR5-expressing neuroblastoma cell-lines with different oncogenic drivers, SK-N-BE(2)-C (MNA), SH-SY5Y (ALK mutant) and SK-N-AS (NRAS mutant) displayed highly inducible β-catenin-TCF/Lef-regulated transcription when treated with recombinant Wnt3a and R-Spondin 2 (Rspo2), with a strong requirement for LGR5/Rspo2 apparent for maximal induction, as Wnt3a/Rspo2 induction of TOPFLASH was at least 5-fold greater than with Wnt3a alone. Here, NRAS is linked to neuroblastoma.