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近因。因此，识别晚期进展的守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终末期进展的快速步伐，为识别晚期癌症进展的调节因子提供了一个出色的模型。我们专注于定义甲状腺癌远处转移灶中独特的基因组改变，并将钙调神经磷酸酶1.4（RCAN1.4）作为一种新的转移抑制因子。随后在其他实体瘤中也报道了这种功能。通过无偏基因组分析和人类组织的验证性研究，以及在人类细胞系，小鼠异种移植物和新开发的基因工程小鼠模型中的功能研究，我们已经确定了Cap-N-Collar转录因子NFE 2L 3（Nrf 3）作为RCAN 1.4丢失诱导的关键下游功能调节因子。此外，NFE 2L 3本身的功能是促进甲状腺癌细胞的生长和侵袭，并与预后不良有关。我们还表明，RCAN1.4缺失和NFE 2L 3过表达与体外和体内免疫活化相关，NFE 2L 3过表达与人甲状腺癌中的容许1型免疫环境相关，IL-8释放和基因表达受NFE 2L 3调节，并且NFE 2L 3直接结合IL 8启动子并调节其活性，提示在甲状腺癌中调节肿瘤-免疫界面的机制作用。进行性甲状腺癌通常与PD 1/PDL 1的过表达或微卫星不稳定性无关，尽管通常有强烈的免疫细胞浸润，因此，检查点抑制剂在很大程度上是无效的。这些数据强调了定义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NFE 2L 3过表达诱导促进甲状腺癌进展的致瘤和促转移免疫环境。

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.