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

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. NR2F2 inducible Gain-of-Function (GoF) was induced for 48h by Doxycycline (1µg/mL) on the human Skin SCC cell lines A431 before chromatin collection.