SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Mutations in SWI/SNF chromatin remodeling complexes are frequent in various cancers, including advanced thyroid cancer.
• BRAF V600E mutations are common drivers in papillary thyroid cancer, impacting tumor progression and differentiation.

Purpose of the Study:

• To investigate the role of SWI/SNF subunit loss in BRAF V600E-mutant thyroid tumors.
• To determine the impact of SWI/SNF mutations on chromatin accessibility, gene expression, and therapeutic response.

Main Methods:

• Utilized mouse models of BRAF V600E-mutant thyroid tumors with specific SWI/SNF subunit (Arid1a, Arid2, Smarcb1) loss.
• Assessed effects on tumor progression, survival, chromatin accessibility, and lineage-specific gene expression.
• Evaluated responses to MAPK pathway inhibition and radioiodine incorporation.

Main Results:

• Thyroid-specific loss of Arid1a, Arid2, or Smarcb1 accelerated tumor progression and reduced survival.
• SWI/SNF subunit loss led to decreased chromatin accessibility at lineage transcription factor binding sites, impairing differentiation and radioiodine uptake.
• Loss of SWI/SNF function created a repressive chromatin state resistant to MAPK inhibition, causing insensitivity to redifferentiation therapies.

Conclusions:

• SWI/SNF complexes are critical for maintaining thyroid cancer differentiation.
• Loss of SWI/SNF subunits confers radioiodine refractoriness and resistance to MAPK inhibitor-based redifferentiation strategies.
• Targeting SWI/SNF function may be crucial for overcoming therapeutic resistance in BRAF-mutant thyroid cancers.