Pluto Biosciences, Inc

GSE147477: SWI/SNF complex mutations promote thyroid tumor progression and resistance to redifferentiation therapy (RNA-seq, Fig2)

Bulk RNA sequencing

Recurrent mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex occur commonly in human cancers of different lineages, including advanced thyroid cancers. Thyroid-specific loss of Arid1a, Arid2 or Smarcb1 in mouse BrafV600E-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. Swi/Snf loss leads to a repressive chromatin state at thyroid lineage transcription factors and their target binding sites, resulting in impaired expression of genes required for thyroid hormone biosynthesis. Thyroid differentiation and response to radioiodine therapy is restored by MAPK inhibitors in mouse BrafV600E-mutant thyroid cancers, which is abrogated in the context of Swi/Snf loss. MAPK inhibitors also failed to restore thyroid differentiation and radioiodide incorporation in patients with BRAFV600E or RAS-mutant tumors with SWI/SNF mutations. SWI/SNF complexes are central to the maintenance of differentiated thyroid function, and their loss confers RAI refractoriness and resistance to MAPK inhibitor-based redifferentiation therapies. SOURCE: Richard Koche (kocher@mskcc.org) - Memorial Sloan Kettering Cancer Center

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