紫外线诱发的前癌性光氧化角化病变（AK）进展到恶性浸润性皮肤鳞状细胞癌（cSCC）和潜在的致命转移性疾病的分子基础仍不清楚。DNA测序研究揭示了大量的突变负担，但尚未揭示疾病进展的机制。在这里，我们对110个患者样本进行RNA测序转录组分析，涵盖了正常的太阳暴露皮肤、AK、原发性和转移性cSCC，发现了从分化状态到祖细胞样状态的疾病连续性。这伴随着上皮分化的主调节因子的协调抑制、上皮分化复合物的动态调节、免疫环境的重塑以及肿瘤特异性角质形成细胞数量的增加。通过对人类cSCC的比较系统分析以及生成基因工程小鼠模型，我们发现连续组合靶向抑制抑癌基因Tgfbr2、Trp53和Notch1，以及激活Ras信号通路可逐步推动cSCC沿着分化到祖细胞方向的进展。综上所述，我们提供了cSCC疾病连续性的全面图谱，并揭示了促进和伴随疾病进展的潜在可操作事件。© 2023. Springer Nature Limited.

The molecular basis of disease progression from UV-induced precancerous actinic keratosis (AK) to malignant invasive cutaneous squamous cell carcinoma (cSCC) and potentially lethal metastatic disease remains unclear. DNA sequencing studies have revealed a massive mutational burden but have yet to illuminate mechanisms of disease progression. Here we perform RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation, dynamic modulation of the epidermal differentiation complex, remodelling of the immune landscape and an increase in the preponderance of tumour specific keratinocytes. Comparative systems analysis of human cSCC coupled with the generation of genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genes Tgfbr2, Trp53, and Notch1 coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis. Taken together we provide a comprehensive map of the cSCC disease continuum and reveal potentially actionable events that promote and accompany disease progression.© 2023. Springer Nature Limited.