Squamous cell carcinomas (SCC), including cutaneous SCCs, are by far the most frequent cancers in humans, accounting for 80% of all newly diagnosed malignancies worldwide. The old dogma that SCC develops exclusively from stem cells (SC) has now changed to include progenitors, transit-amplifying and differentiated short-lived cells. Accumulation of specific oncogenic mutations is required to induce SCC from each cell population. Whilst as fewer as one genetic hit is sufficient to induce SCC from a SC, multiple events are additionally required in more differentiated cells. Interestingly, the level of differentiation correlates with the number of transforming events required to induce a stem-like phenotype, a long-lived potential and a tumourigenic capacity in a progenitor, a transient amplifying or even in a terminally differentiated cell. Furthermore, it is well described that SCCs originating from different cells of origin differ not only in their squamous differentiation status but also in their malignant characteristics. This review summarises recent findings in cutaneous SCC and highlights transforming oncogenic events in specific cell populations. It underlines oncogenes that are restricted either to stem or differentiated cells, which could provide therapeutic target selectivity against heterogeneous SCC. This strategy may be applicable to SCC from different body locations, such as head and neck SCCs, which are currently still associated with poor survival outcomes.
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