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The BRD4-NUT Fusion Alone Drives Malignant Transformation of NUT Carcinoma
R Taylor Durall1, Julianna Huang1, Luke Wojenski2
1Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Abstract:
NUT carcinoma (NC) is an aggressive squamous carcinoma defined by the BRD4-NUT fusion oncoprotein. Routinely effective systemic treatments are unavailable for most NC patients. The lack of an adequate animal model precludes identifying and leveraging cell-extrinsic factors therapeutically in NC. Here, we created a genetically engineered mouse model (GEMM) of NC that forms a Brd4::NUTM1 fusion gene upon tamoxifen induction of Sox2-driven Cre. The model displayed complete disease penetrance, with tumors arising from the squamous epithelium weeks after induction and all mice succumbing to the disease shortly thereafter. Closely resembling human NC (hNC), GEMM tumors (mNC) were poorly differentiated squamous carcinomas with high expression of MYC that metastasized to solid organs and regional lymph nodes. Two GEMM-derived cell lines were developed whose transcriptomic and epigenetic landscapes harbored key features of primary GEMM tumors. Importantly, GEMM tumor and cell line transcriptomes co-classified with those of human NC. BRD4-NUT also blocked differentiation and maintained the growth of mNC as in hNC. Mechanistically, GEMM primary tumors and cell lines formed large histone H3K27ac-enriched domains, termed megadomains, that were invariably associated with the expression of key NC-defining proto-oncogenes, Myc and Trp63. Small-molecule BET bromodomain inhibition (BETi) of mNC induced differentiation and growth arrest and prolonged survival of NC GEMMs, as it does in hNC models. Overall, tumor formation in the NC GEMM is definitive evidence that BRD4-NUT alone can potently drive the malignant transformation of squamous progenitor cells into NC.
Significance:
The development of an immunocompetent model of NUT carcinoma that closely mimics the human disease provides a valuable global resource for mechanistic and preclinical studies to improve treatment of this incurable disease.
Insights
A new genetically engineered mouse model (GEMM) of NUT carcinoma (NC) was developed. This model, driven by the BRD4-NUT fusion, mimics human NC and shows promise for preclinical studies and improved treatment strategies for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- NUT carcinoma (NC) is an aggressive squamous cell carcinoma characterized by the BRD4-NUT fusion oncoprotein.
- Current systemic treatments for NC are often ineffective, and a lack of adequate animal models hinders therapeutic development.
- Understanding the cell-extrinsic factors and developing effective treatments for NC remains a significant challenge.
Purpose of the Study:
- To create a genetically engineered mouse model (GEMM) of NUT carcinoma (NC) that accurately replicates human disease characteristics.
- To utilize this model for investigating the mechanisms driving NC and for preclinical testing of therapeutic interventions.
- To establish a valuable resource for the research community studying this aggressive and often fatal cancer.
Main Methods:
- Development of a GEMM of NC by inducing a Brd4::NUTM1 fusion gene in Sox2-driven Cre expressing mice.
- Characterization of tumor formation, histology, gene expression (transcriptomics), and epigenetic landscapes in the GEMM.
- Establishment and analysis of GEMM-derived cell lines.
- Evaluation of the therapeutic efficacy of small-molecule BET bromodomain inhibition (BETi).
Main Results:
- The NC GEMM exhibited complete disease penetrance, with tumors arising from squamous epithelium and leading to mortality.
- GEMM tumors (mNC) closely resembled human NC (hNC), displaying poor differentiation, high MYC expression, and metastasis.
- GEMM-derived cell lines mirrored the transcriptomic and epigenetic features of primary GEMM tumors and human NC.
- BET inhibition induced differentiation, growth arrest, and prolonged survival in NC GEMMs, similar to hNC models.
- The study confirmed BRD4-NUT as a potent driver of malignant transformation in squamous progenitor cells.
Conclusions:
- The developed NC GEMM serves as a robust and accurate preclinical model for human NUT carcinoma.
- This model recapitulates key features of human NC, including its aggressive nature and response to BET inhibition.
- The findings validate BRD4-NUT as the primary oncogenic driver and highlight the therapeutic potential of BET inhibitors for NC.
- The immunocompetent GEMM provides a crucial resource for future mechanistic and therapeutic studies of NC.
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