Tumor cells are subjected to evolutionary selection pressures during progression from initiation to metastasis.,We analyzed the clonal evolution of squamous skin carcinomas induced by DMBA/TPA treatment using the K5CreER-Confetti mouse and stage-specific lineage tracing.,We show that benign tumors are polyclonal, but only one population contains the Hras driver mutation.,Benign papillomas are therefore monoclonal in origin, but recruit neighboring epithelial cells during growth.,Papillomas that never progress to malignancy retain several distinct clones, whereas progression to carcinoma is associated with a clonal sweep.,Newly generated clones within carcinomas demonstrate intratumoral invasion and clonal intermixing, often giving rise to metastases containing two or more distinct clones derived from the matched primary tumor.,These data demonstrate that late stage tumor progression and dissemination are governed by evolutionary selection pressures that operate at a multicellular level, and thus differ from the clonal events that drive initiation and the benign-malignant transition.
Cutaneous squamous cell carcinoma (cuSCC) comprises 15-20% of all skin cancers, accounting for over 700,000 cases in USA annually.,Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK).,To identify potential targets for molecularly targeted chemoprevention, here we perform integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar ultraviolet radiation-driven Hairless mouse model.,We identify the major transcriptional drivers of this progression sequence, showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition.,Our data validate the use of this ultraviolet radiation-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.,Cutaneous squamous cell of the skin is a common neoplasm that frequently arises from precancerous actinic keratoses.,Here, the authors carry out genomic analysis on matched sets of human lesions and compare with those in ultraviolet treated mice and identify conserved drivers of tumour development.