The BRD4-NUT Fusion Alone Drives Malignant Transformation of NUT Carcinoma.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 Dec 2023
01 Dec 2023
Historique:
received:
24
08
2023
revised:
26
09
2023
accepted:
06
10
2023
medline:
4
12
2023
pubmed:
11
10
2023
entrez:
11
10
2023
Statut:
ppublish
Résumé
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. 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.
Identifiants
pubmed: 37819236
pii: 729540
doi: 10.1158/0008-5472.CAN-23-2545
pmc: PMC10690098
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Nuclear Proteins
0
Oncogene Proteins, Fusion
0
Transcription Factors
0
Nutm1 protein, mouse
0
Brd4 protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3846-3860Subventions
Organisme : NIH HHS
ID : DP5 OD024587
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL157174
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA124633
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA285308
Pays : United States
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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