Roh V, Hiou-Feige A, Misetic V, et al. - Using shRNA-mediated knockdown, investigators illustrated a minimal influence of Forkhead Box (FOX)M1 on proliferation and migration of squamous cell carcinomas of the head and neck (HNSCC) cell lines under standard cell culture conditions and explained the role of FOXM1 in HNSCC cell lines using cell culture and tumor xenograft models. Nonetheless, in 3D culture and xenograft tumor models, FOXM1 knockdown, led to decreased proliferation, reduced invasion, and a more differentiated-like phenotype, showing a context-dependent modulation of FOXM1 activity in HNSCC cells. In HNSCC cell lines, through ectopic overexpression of FOXM1, a decreased expression of cutaneous-type keratin K1 and involucrin as a marker of squamous differentiation was exhibited, strengthening the role of FOXM1 in the modulation of anomalous differentiation in HNSCC. In conclusion, data give a robust rationale for targeting FOXM1 in HNSCC.