In order to study the functional role of mutated PLXNB2 in CUP development, we exploited a validated experimental model in culture, that is, cancer stem cell‐enriched spheroids derived from CUP biopsies (Verginelli et al, 2021), which have been previously demonstrated to faithfully recapitulate the original CUP phenotype and genetic landscape, including PLXNB2 mutation. This evidence concerns the gene PLXNB2 and cancer.