RCAN 1.4 metastasis suppressor in thyroid cancer

进行性转移是大多数实体瘤患者癌症相关死亡的直接原因。因此，确定晚期进展的看门人并确定其作用机制至关重要。甲状腺癌由于其典型的长潜伏期和往往快速的终末期进展，为识别晚期癌症进展的调节因子提供了一个杰出的模型。我们专注于定义甲状腺癌远处转移病变中独特的基因组改变，并鉴定了钙调磷酸酶1.4调节因子（RCAN1.4）作为一种新的转移抑制因子。这一功能随后在其他实体瘤中也有报道。通过对人类组织的无偏基因组分析和验证性研究，以及对人类细胞系、小鼠异种移植物和新开发的基因工程小鼠模型的功能研究，我们已经确定了Cap-N-Collar转录因子NFE2L3 （Nrf3）是RCAN1.4缺失诱导的关键下游功能调节剂。此外，NFE2L3本身具有促进甲状腺癌细胞生长和侵袭的功能，与不良预后相关。我们还发现，RCAN1.4缺失和NFE2L3过表达与体外和体内免疫激活有关，NFE2L3过表达与人甲状腺癌中允许的1型免疫环境有关，IL-8的释放和基因表达受NFE2L3调控，NFE2L3直接与IL-8启动子结合并调节其活性，提示在甲状腺癌中具有调节肿瘤-免疫界面的机制作用。进行性甲状腺癌通常与PD1/PDL1过表达或微卫星不稳定性无关，尽管免疫细胞浸润很强，因此检查点抑制剂在很大程度上无效。这些数据强调了确定调节这种肿瘤类型进展的免疫环境调节因子的重要性。总体假设是RCAN1.4缺失和NFE2L3过表达诱导了致瘤性和促转移性免疫环境，促进了甲状腺癌的进展。

Progressive metastasis is the proximate cause of cancer-related mortality for the majority of patients with solid tumors. Identifying gatekeepers of late stage progression and defining their mechanisms of action is therefore crucial. Thyroid cancer provides an outstanding model to identify regulators of late stage cancer progression due to its typical long latency and the often rapid pace of end-stage progression. We have focused on defining unique genomic alterations in distant metastatic lesions in thyroid cancer and identified Regulator of Calcineurin 1.4 (RCAN1.4) as a new metastasis suppressor. This function has subsequently been reported in other solid tumors. Through a combination of unbiased genomic analysis and confirmatory studies of human tissues, and functional studies in human cell lines, mouse xenografts, and newly-developed genetically engineered mouse models, we have identified the Cap-N-Collar transcription factor, NFE2L3 (Nrf3) as a critical downstream functional regulator induced by RCAN1.4 loss. In addition, NFE2L3 itself functions to promote thyroid cancer cell growth and invasion and is associated with poor prognosis. We also have shown that RCAN1.4 loss and NFE2L3 overexpression are associated with immune activation in vitro and in vivo, that overexpression of NFE2L3 is associated with a permissive type 1 immune environment in human thyroid cancer, that IL-8 release and gene expression are regulated by NFE2L3, and that NFE2L3 directly binds to the IL8 promoter and regulates its activity, suggesting a mechanistic role in regulation the tumor-immune interface in thyroid cancer. Progressive thyroid cancers are typically not associated with overexpression of PD1/PDL1 or microsatellite instability, despite often robust immune cell infiltrate, thus, checkpoint inhibitors have been largely ineffective. These data highlight the importance of defining regulators of the immune environment that regulate progression of this tumor type. The overall hypothesis is that RCAN1.4 loss and NFE2L3 overexpression induce a tumorigenic and pro-metastatic immune environment that facilitates thyroid cancer progression.