Project description:We created a genetically engineered mouse model (GEMM) of NC that forms a Brd4-NUTM1 fusion gene upon tamoxifen-induction of Sox2-driven Cre. Two GEMM-derived cell lines were developed whose transcriptomic and epigenetic landscapes, characterized by RNAseq and CUT&RUN, show striking overlap with those of primary GEMM tumors. GEMM primary tumor and cell lines form very large H3K27ac-enriched super-enhancers that are unique to hNC, termed megadomains, that are invariably associated with key hNC-defining transcriptional oncogenic targets, Myc and Trp63.
Project description:NUT carcinoma (NC) is a highly aggressive subtype of squamous carcinoma driven by the BRD4-NUT fusion oncoprotein. Closely resembling human NC (hNC), GEMM tumors (mNC) are poorly differentiated squamous carcinomas that express high levels of MYC and metastasize to organs (liver, lung) and regional lymph nodes. Two GEMM-derived cell lines were developed whose transcriptomic and epigenetic landscapes, characterized by RNAseq and CUT&RUN, show striking overlap with those of primary GEMM tumors. As in hNC, BRD4-NUT functions to block differentiation and maintain growth of mNC, as evidenced by BRD4-NUT knockdown and treatment of mNC cell lines with BET bromodomain inhibitors (BETi). Mechanistically, GEMM primary tumor and cell lines form very large H3K27ac-enriched super-enhancers that are unique to hNC, termed megadomains, that are invariably associated with key hNC-defining transcriptional oncogenic targets, Myc and Trp63.
