Cell type-specific chromatin states differentially prime squamous cell carcinoma tumor-initiating cells for epithelial to mesenchymal transition

Epithelial to mesenchymal transition (EMT) in cancer cells has been associated with metastasis, stemness and resistance to therapy. The reason why some tumors undergo EMT and other not might reflect intrinsic properties of their cell of origin, although this possibility is largely unexplored. By targeting the same oncogenic mutations to discrete skin compartments, we show cell type-specific chromatin and transcriptional states differentially prime tumors to EMT. Squamous cell carcinomas (SCCs) derived from intrafollicular epidermis (IFE) are generally well-differentiated, while hair follicle (HF) stem cell-derived SCCs frequently exhibit EMT, efficiently form secondary tumors, and possess increased metastatic potential. Transcriptional and epigenomic profiling revealed IFE and HF tumor-initiating cells possess distinct chromatin landscapes and gene regulatory networks associated with tumorigenesis and EMT that correlate with accessibility of key epithelial and EMT transcription factor binding sites. These findings highlight the importance of chromatin states and transcriptional priming in dictating tumor phenotypes and EMT.

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Latil M, Nassar D, Beck B, Boumahdi S, Wang L, Brisebarre A, Dubois C, Nkusi E, Lenglez S, Checinska A, Vercauteren Drubbel A, Devos M, Declercq W, Yi R, Blanpain C