NR2F2 controls malignant squamous cell carcinoma state by promoting stemness and invasion and repressing differentiation II. NR2F2 controls malignant squamous cell carcinoma state by promoting stemness and invasion and repressing differentiation II

The non-genetic mechanisms required to sustain malignant tumor state are poorly understood. During the transition from benign tumors to malignant carcinoma, tumor cells need to repress differentiation and acquire invasive features. Using transcriptional profiling of cancer stem cells (CSC) from benign tumors and malignant skin squamous cell carcinoma (SCC), we identified the nuclear receptor NR2F2 as uniquely expressed in malignant SCC. Using genetic gain- and loss-of-function in vivo, we show that NR2F2 is essential for promoting the malignant tumor state by controlling tumor stemness and maintenance in mouse and human SCC. We demonstrate that NR2F2 promotes tumor cell proliferation, epithelial-mesenchymal transition (EMT) and invasive features, while repressing tumor differentiation and immune cell infiltration by regulating a common transcriptional program in mouse and human SCCs. Altogether, we identify NR2F2 as a key regulator of malignant CSC functions that promotes tumor renewal and restricts differentiation to sustain malignant tumor state. Overall design: FACS isolated CD34+Epcam+tumor cells from DMBA/TPA induced papillomas (benign skin SCC) and carcinomas (malignant skin SCC)

目前学界对维持恶性肿瘤状态所需的非遗传机制仍知之甚少。在从良性肿瘤向恶性癌转变的进程中，肿瘤细胞需抑制分化并获得侵袭性表型。本研究针对良性肿瘤来源的癌症干细胞（cancer stem cells, CSC）与恶性皮肤鳞状细胞癌（skin squamous cell carcinoma, SCC）开展转录组分析，鉴定出核受体NR2F2在恶性SCC中呈特异性表达。通过体内功能获得与功能缺失实验，我们证实NR2F2可通过调控小鼠及人类SCC中的肿瘤干细胞干性与维持状态，在促进恶性肿瘤状态形成中发挥核心作用。研究表明，NR2F2可通过调控小鼠与人类SCC共有的转录程序，促进肿瘤细胞增殖、上皮间质转化（epithelial-mesenchymal transition, EMT）及侵袭性特征，同时抑制肿瘤分化与免疫细胞浸润。综上，本研究鉴定NR2F2为恶性CSC功能的关键调控因子，其可促进肿瘤更新并限制分化，从而维持恶性肿瘤状态。
总体设计：通过荧光激活细胞分选（Fluorescence-Activated Cell Sorting, FACS）从DMBA/TPA诱导的乳头状瘤（良性皮肤鳞状细胞癌）与癌（恶性皮肤鳞状细胞癌）中分离得到CD34+Epcam+肿瘤细胞。