Squamous cell carcinomas are triggered by marked elevation of RAS–MAPK signalling and progression from benign papilloma to invasive malignancy^1,2,3,4. At tumour–stromal interfaces, a subset of tumour-initiating progenitors, the cancer stem cells, obtain increased resistance to chemotherapy and immunotherapy along this pathway^5,6. The distribution and changes in cancer stem cells during progression from a benign state to invasive squamous cell carcinoma remain unclear. Here we show in mice that, after oncogenic RAS activation, cancer stem cells rewire their gene expression program and trigger self-propelling, aberrant signalling crosstalk with their tissue microenvironment that drives their malignant progression. The non-genetic, dynamic cascade of intercellular exchanges involves downstream pathways that are often mutated in advanced metastatic squamous cell carcinomas with high mutational burden⁷. Coupling our clonal skin HRAS^G12V mouse model with single-cell transcriptomics, chromatin landscaping, lentiviral reporters and lineage tracing, we show that aberrant crosstalk between cancer stem cells and their microenvironment triggers angiogenesis and TGFβ signalling, creating conditions that are conducive for hijacking leptin and leptin receptor signalling, which in turn launches downstream phosphoinositide 3-kinase (PI3K)–AKT–mTOR signalling during the benign-to-malignant transition. By functionally examining each step in this pathway, we reveal how dynamic temporal crosstalk with the microenvironment orchestrated by the stem cells profoundly fuels this path to malignancy. These insights suggest broad implications for cancer therapeutics.

鳞状细胞癌是由 RAS-MAPK 信号显着升高和从良性乳头状瘤进展为浸润性恶性肿瘤^1,2,3,4引发的。在肿瘤-间质界面，肿瘤起始祖细胞的一个子集，即癌症干细胞，沿着这条通路获得对化学疗法和免疫疗法的更高抵抗力^5,6. 从良性状态发展为浸润性鳞状细胞癌期间癌症干细胞的分布和变化仍不清楚。在这里，我们在小鼠身上显示，在致癌 RAS 激活后，癌症干细胞重新连接它们的基因表达程序，并触发自我推进的、异常的信号与其组织微环境的串扰，从而驱动它们的恶性进展。细胞间交换的非遗传动态级联涉及下游通路，这些通路通常在具有高突变负荷的晚期转移性鳞状细胞癌中发生突变⁷。耦合我们的克隆皮肤HRAS ^G12V通过使用单细胞转录组学、染色质美化、慢病毒报告基因和谱系追踪的小鼠模型，我们表明癌症干细胞与其微环境之间的异常串扰会触发血管生成和 TGFβ 信号传导，从而创造有利于劫持瘦素和瘦素受体信号传导的条件，这在turn 在良性向恶性转变期间启动下游磷酸肌醇 3 激酶 (PI3K)–AKT–mTOR 信号。通过从功能上检查该通路中的每个步骤，我们揭示了干细胞与微环境的动态时间串扰如何深刻地助长了这条通往恶性肿瘤的通路。这些见解对癌症治疗具有广泛的意义。