Cutaneous squamous cell carcinoma (cSCC) leads to significant morbidity for patients with progression and metastases. However, the molecular underpinnings of these tumors are still poorly understood. Dissecting human cSCC pathogenesis amplifies the exigence for preclinical models that mimic invasion and nodal spread. This review discusses the currently available models, including two- and three-dimensional tissue cultures, syngeneic and transgenic mice, and cell line-derived and patient-derived xenografts. We further highlight studies that have utilized the different models, considering how they recapitulate specific hallmarks of cSCC. Finally, we discuss the advantages, limitations and future research directions.
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