Molecular Pathophysiology of Thyroid Cell Growth

摘要： 低分化(PDTC)和间变性甲状腺癌(ATC)发生率较高 SWI/SNF(BAF和PBAF)染色质亚单位编码基因的突变 重塑复合体。此外，还发现了睡美人转座子突变筛选 染色质修饰物的破坏，包括SwI/SNF亚基，显著地协同作用 致癌的HRA进展为PDTC。SWI/SNF综合体支持终端 在多个环境中的分化和它的丧失可以促进干细胞样特性。强有力的 抑制MAPK信号显著增强甲状腺分化基因的表达， 增加小鼠和患者对放射性碘(RAI)的摄取和对RAI治疗的反应 与MAPK信号效应器的突变有关。我们推测SWI/SNF的中断可能会锁定 甲状腺细胞进入不再通过MAPK途径可逆的去分化状态 封锁。我们发现ARID1A、ARID2和SMARCB1的纯合性丢失在 BRAFV600E可导致去分化、PDTC和ATCs的发生，降低存活率。 尽管Swi/Snf亚基丢失导致更紧密且难以接近的染色质景观， 矛盾的是，它还增加了染色体对富含DNA的部位的可及性 预测转录程序激活的基序，介导疾病进展和 转分化，并产生潜在的治疗依赖。例如，这些 肿瘤对Hedgehog通路有很强的激活作用，并且对Gli非常敏感 拮抗剂GANT61，但不对该途径的上游抑制物起作用。我们现在将追查 1.研究ARID1A、ARID2和SMARCB1基因缺失对甲状腺的影响 宝石模型以及染色质和转录图谱中的肿瘤发生。2.识别 BRAF突变甲状腺中ARID1A、ARID2和SMARCB1缺失引起的新依赖性 癌症，并检验SWI/SNF缺失增加MAPK转录输出的假设 在其信号效应器介导的磷酸化级联反应的远端。我们还将确定 Swi/SNF的缺失是否平衡了细胞向非甲状腺系的反式分化，以及 探索其中涉及的机制。3.确定SWI/SNF功能丧失是否损害 MAPK通路抑制剂对BRAF诱导的甲状腺分化的恢复作用 癌症，如果是这样的话，如果这可以通过GANT61，BET DOMAIN或EZH2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.