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Figure S7 from SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies

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posted on 2023-04-03, 23:21 authored by Mahesh Saqcena, Luis Javier Leandro-Garcia, Jesper L.V. Maag, Vatche Tchekmedyian, Gnana P. Krishnamoorthy, Prasanna P. Tamarapu, Vera Tiedje, Vincent Reuter, Jeffrey A. Knauf, Elisa de Stanchina, Bin Xu, Xiao-Hui Liao, Samuel Refetoff, Ronald Ghossein, Ping Chi, Alan L. Ho, Richard P. Koche, James A. Fagin

Impact of acute MAPK blockade on chromatin accessibility in TBraf and TBraf/Swi-Snf deficient tumors.

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Translational Research Oncology Training program

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ARTICLE ABSTRACT

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 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. As compared with normal thyrocytes, BRAFV600E-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. 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 BRAF-mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade.This article is highlighted in the In This Issue feature, p. 995

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