期刊
SCIENCE ADVANCES
卷 6, 期 29, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aaz3440
关键词
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资金
- NIH [R01-CA180692]
- Children's Neuroblastoma Cancer Foundation
- Friends of DFCI award
- Friends for Life Fellowship from Dana-Farber Cancer Institute
- Rally Foundation for Childhood Cancer Research
- Friends for Life Neuroblastoma Fellowship from Dana-Farber Cancer Institute
- Charles A. King Trust
- Claudia Adams Barr Innovative Basic Science research program
- Damon-Runyon Cancer Research Foundation [DRSG-24-18]
- Alex's Lemonade Stand Foundation
- CureSearch for Children's Cancer Foundation
Mutations in genes encoding SWI/SNF chromatin remodeling complexes are found in approximately 20% of all human cancers, with ARID1A being the most frequently mutated subunit. Here, we show that disruption of ARID1A homologs in a zebrafish model accelerates the onset and increases the penetrance of MYCN-driven neuroblastoma by increasing cell proliferation in the sympathoadrenal lineage. Depletion of ARID1A in human NGP neuroblastoma cells promoted the adrenergic-to-mesenchymal transition with changes in enhancer-mediated gene expression due to alterations in the genomic occupancies of distinct SWI/SNF assemblies, BAF and PBAF. Our findings indicate that ARID1A is a haploinsufficient tumor suppressor in MYCN-driven neuroblastoma, whose depletion enhances tumor development and promotes the emergence of the more drug-resistant mesenchymal cell state.
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