Speaker
Description
The nongenetic 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 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 of function 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 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 cancer stem cell functions that promotes tumor renewal and restricts differentiation to sustain a malignant tumor state.
References
- Alam, M. & Ratner, D. Cutaneous squamous-cell carcinoma. N. Engl. J. Med.
344, 975–983 (2001). - Sanchez-Danes, A. & Blanpain, C. Deciphering the cells of origin of
squamous cell carcinomas. Nat. Rev. Cancer 18, 549–561 (2018). - Owens, D. M. & Watt, F. M. Contribution of stem cells and diferentiated
cells to epidermal tumors. Nat. Rev. Cancer 3, 444–451 (2003). - Perez-Losada, J. & Balmain, A. Stem-cell hierarchy in skin cancer. Nat. Rev.
Cancer 3, 434–443 (2003). - Abel, E. L., Angel, J. M., Kiguchi, K. & DiGiovanni, J. Multi-stage chemical
carcinogenesis in mouse skin: fundamentals and applications. Nat. Protoc. 4,
1350–1362 (2009). - Kemp, C. J. Multistep skin cancer in mice as a model to study the evolution
of cancer cells. Semin. Cancer Biol. 15, 460–473 (2005).
| Keywords | cancer, stemness, differentiation, NR2F2, transcriptomics, chromatin landscape, EMT, tumour state |
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