Future studies will be required: (i) to confirm this concept, (ii) to unravel relevant SOX2-related signaling and gene regulatory networks, and (iii) to address the question of whether detection of SOX2-negative tumor cells at the invasive front of primary HNSCC predicts the risk for treatment failure and subsequent loco-regional and/or distant relapse. The gene discussed is SOX2; the disease is head and neck squamous cell carcinoma.