Beyond infection: Innate immune receptors as an emerging brake on metastasis

超越感染：先天免疫受体作为转移的新刹车 摘要 先天免疫信号是哺乳动物抵御病原体的关键防御系统。重要的是，这些信号 即使在感染领域之外，网络也与人类疾病密切相关。先天的这一方面 豁免权在很大程度上仍然难以捉摸，这构成了我研究的主题。我的论文主要集中在 伪激酶核糖核酸酶L，在感染过程中最强烈的激活。核糖核酸酶L是由2‘-5’连锁触发的 异构体RNA，由寡腺苷合成酶(OAS)在感应双链RNA(DsRNA)时产生 通常被认为来自RNA病毒。核糖核酸酶L是应对细菌和病毒必不可少的 感染。核糖核酸酶L也是细胞周期进程、分化和凋亡过程的主要调节者 在癌症中经常被错误地调节。值得注意的是，许多核糖核酸酶L突变使男性患上 遗传性前列腺癌。此外，我的初步结果发现，抑制核糖核酸酶L的表达 与乳腺癌侵袭性的增加密切相关。核糖核酸酶L在肿瘤抑制中的作用 是惊人的，但其分子机制尚不清楚。我的工作确定了人类核糖核酸酶的第一个细胞靶点 L在室外感染，应对了自1980年发现核糖核酸酶L以来面临的挑战。巧合的是，RNase L的靶点与成熟的肿瘤抑制因子miR-200和他们的一个 共同靶点是肿瘤转移的主要调控因子，ZEB1。这些结果表明一个直接的分子 核糖核酸酶L在控制转移中的作用机制，我试图在我的F99期研究这一点。在……里面 此外，我将分离内源性dsRNA，预计在癌症中会升高，它可以进入 OAS/核糖核酸酶L轴。因此，我将测试OAS是否不仅是针对病毒的dsRNA监视机制，而且 还有癌症。这项工作将揭示猪瘟病毒主要非免疫功能的分子机制。 OAS/核糖核酸酶L轴，为抗转移的新诊断和治疗策略提供信息。我的论文 引导我进入癌症先天免疫这一新兴领域，并为我的博士后研究提供了种子 方向。经过严格的训练和为人类健康服务的令人兴奋的潜力，我正处于完美的轨道上 在癌症免疫学的前沿开始独立的职业生涯。

BEYOND INFECTION: INNATE IMMUNE RECEPTORS AS AN EMERGING BRAKE ON METASTASIS ABSTRACT Innate immune signaling is a key mammalian defense against pathogens. Importantly, these signaling networks are critically linked to human disease even outside the realm of infections. This facet of innate immunity remains largely elusive and forms the subject of my research. My thesis focuses on the pseudokinase RNase L, which is most strongly activated during infection. RNase L is triggered by 2'-5'-linked iso-RNAs, produced by oligoadenylate synthetases (OASs) upon sensing double-stranded RNA (dsRNA) commonly thought to come from RNA viruses. RNase L is essential for coping with bacterial and viral infections. RNase L is also a major regulator of cell cycle progression, differentiation, and apoptosis, processes often misregulated in cancers. Notably, many RNase L mutations predispose men to an elevated risk of inherited prostate cancer. Moreover, my preliminary results uncover that dampened RNase L expression strongly correlates with increased breast cancer aggressiveness. The effect of RNase L on tumor suppression is striking but its molecular mechanism is unclear. My work identifies the first cellular targets of human RNase L outside infection, tackling a challenge faced since the discovery of RNase L in 1980. Serendipitously, RNase L targets perfectly overlap with those of a well-established tumor-suppressor, miR-200, and one of their common targets is the master regulator of metastasis, ZEB1. These results suggest a direct molecular mechanism for the role of RNase L in controlling metastasis, which I seek to examine during my F99 phase. In addition, I will isolate endogenous dsRNAs, predicted to be elevated in cancers, which can feed into the OAS/RNase L axis. Thus, I will test if OASs are a dsRNA surveillance mechanism against not only viruses but also cancer. This work will uncover the molecular mechanism for a major non-immune function of the OAS/RNase L axis, informing novel diagnostic and therapeutic strategies against metastasis. My thesis initiates me into the emerging field of innate immunity in cancer and seeds my postdoctoral research directions. With rigorous training and an exciting potential to serve human health, I am on a perfect trajectory to launch an independent career at the forefront of cancer immunology.