As cell lines cannot entirely recapitulate the multifaceted effect of NOTCH signaling in clinically diverse HNSCC tumors from different anatomical sites that may or may not contain oncogenic HPV, and from patients that have had varied levels of tobacco smoke exposure, continuous generation and analysis of patient-derived xenografts and alternative cost-effective preclinical models, such as three-dimensional organoids, may allow characterization of the molecular features that define the contextual functional role of DCLK1 in regulating NOTCH signaling. The gene discussed is DCLK1; the disease is head and neck squamous cell carcinoma.