Molecular Pathophysiology of Thyroid Cell Growth

摘要： 低分化（PDTC）和间变性甲状腺癌（ATC）的发生率很高， 编码SWI/SNF（BAF和PBAF）染色质亚基的基因突变 重塑复合体此外，睡美人转座子诱变筛选发现， 包括Swi/Snf亚基在内的染色质修饰剂的破坏， 致癌Hras进展为PDTC。SWI/SNF综合体支持终端 在多种情况下的分化及其丧失可以促进干细胞样性质。强效 MAPK信号传导的抑制显著增加甲状腺分化基因的表达， 增加小鼠和患者的放射性碘（RAI）摄取和对RAI治疗的反应 MAPK信号效应子的突变。我们推测SWI/SNF的中断可能会锁定 甲状腺细胞进入MAPK途径不再可逆的去分化状态 封锁我们发现，Arid 1a，Arid 2和Smarcb 1的纯合缺失在 BrafV 600 E导致去分化、PDTC和ATC的发展以及存活率降低。 虽然Swi/Snf亚基缺失导致更紧凑和不可接近的染色质景观， 矛盾的是，它也增加了染色体对DNA富集位点的可接近性， 预测介导疾病进展的转录程序的激活的基序， 转分化，并产生潜在的治疗依赖性。例如，这些 肿瘤具有Hedgehog通路的强烈激活和对Gli的高度敏感性， 拮抗剂GANT 61，但不是该途径的上游抑制剂。我们现在将继续 以下目标：1.研究Arid 1a、Arid 2和Smarcb 1缺失对甲状腺的影响 肿瘤发生的GEM模型和染色质和转录景观。2.识别 Braf突变型甲状腺中Arid 1a、Arid 2和Smarcb 1缺失引起的新的依赖性 癌症，并测试假设，Swi/Snf损失增加MAPK转录输出 在由其信号效应物介导的磷酸化级联反应的远端。我们还将确定 Swi/Snf缺失是否使细胞向非甲状腺谱系转分化，以及 探索其中的机制。3.确定Swi/Snf功能丧失是否会损害 MAPK通路抑制剂恢复Braf驱动甲状腺分化的能力 癌症，如果是这样，如果这可以通过GANT 61，BET结构域或EZH 2抑制剂恢复。

Abstract: Poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC) have a high frequency of mutations of genes encoding subunits of the SWI/SNF (BAF and PBAF) chromatin remodeling complexes. Moreover, a Sleeping Beauty transposon mutagenesis screen found that disruptions of chromatin modifiers, including Swi/Snf subunits, significantly cooperate with oncogenic Hras in progression to PDTC. The SWI/SNF complex supports terminal differentiation in multiple contexts and its loss can promote stem cell-like properties. Potent inhibition of MAPK signaling markedly augments expression of thyroid differentiation genes, increases radioactive iodine (RAI) uptake and responses to RAI therapy in mice and in patients with mutations of MAPK signaling effectors. We speculate that disruptions of SWI/SNF may lock thyroid cells into a dedifferentiated state that is no longer reversible by MAPK pathway blockade. We found that homozygous loss of Arid1a, Arid2 and Smarcb1 in the context of BrafV600E results in dedifferentiation, development of PDTC and ATCs and decreased survival. Although Swi/Snf subunit loss results in a more compact and inaccessible chromatin landscape, it paradoxically also increases chromosome accessibility to sites that are enriched for DNA motifs that predict for activation of transcriptional programs mediating disease progression and trans-differentiation, and generate potential therapeutic dependencies. For instance, these tumors have a robust activation of the Hedgehog pathway and exquisite sensitivity to the Gli antagonist GANT61, but not to upstream inhibitors of the pathway. We will now pursue the following aims: 1. Investigate the impact of Arid1a, Arid2 and Smarcb1 loss on thyroid tumorigenesis in GEM models and on the chromatin and transcriptional landscape. 2. Identify novel dependencies arising from Arid1a, Arid2 and Smarcb1 loss in Braf-mutant thyroid cancers, and test the hypothesis that Swi/Snf loss augments the MAPK transcriptional output distal to the phosphorylation cascade mediated by its signaling effectors. We will also determine whether Swi/Snf loss poises cells to trans-differentiate towards non-thyroidal lineages, and explore the mechanisms involved. 3. Determine whether loss of Swi/Snf function impairs the ability of MAPK pathway inhibitors to restore thyroid differentiation in Braf-driven thyroid cancers, and if so, if this can be restored by GANT61, BET domain or EZH2 inhibitors.