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

• Published in: Cancer discovery Vol. 11; no. 5; p. 1158
• Main Authors: Saqcena, Mahesh, Leandro-Garcia, Luis Javier, Maag, Jesper L V, Tchekmedyian, Vatche, Krishnamoorthy, Gnana P, Tamarapu, Prasanna P, Tiedje, Vera, Reuter, Vincent, Knauf, Jeffrey A, de Stanchina, Elisa, Xu, Bin, Liao, Xiao-Hui, Refetoff, Samuel, Ghossein, Ronald, Chi, Ping, Ho, Alan L, Koche, Richard P, Fagin, James A
• Format: Journal Article
• Language: English
• Published: United States 01-05-2021
• Subjects: Animals; Cell Line, Tumor; Cellular Reprogramming Techniques; Chromosomal Proteins, Non-Histone - genetics; Disease Models, Animal; Mice; Mice, Inbred Strains; Mutation; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Transcription Factors - genetics
• ISSN: 2159-8290
• DOI: 10.1158/2159-8290.CD-20-0735

Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of
, or
in mouse BRAF
-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAF
-mutant mouse papillary thyroid cancers have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid-differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition. Loss of individual SWI/SNF subunits in BRAF tumors leads to a repressive chromatin state that cannot be reversed by MAPK pathway blockade, rendering them insensitive to its redifferentiation effects. Our results show that SWI/SNF complexes are central to the maintenance of differentiated function in thyroid cancers, and their loss confers radioiodine refractoriness and resistance to MAPK inhibitor-based redifferentiation therapies. SIGNIFICANCE: Reprogramming cancer differentiation confers therapeutic benefit in various disease contexts. Oncogenic BRAF silences genes required for radioiodine responsiveness in thyroid cancer. Mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage specification genes in
-mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade.
.