Cellular and molecular mechanism of Hippo signaling in suppressing liver tumor formation

总结 最近的研究扩大了炎症是肿瘤进展的关键组成部分的概念。是 现在清楚的是，肿瘤微环境主要由炎症细胞协调，是不可或缺的 参与肿瘤过程，促进增殖、存活和迁移。在过去的几十年里， 免疫疗法在治疗癌症中变得越来越重要。因此，迫切需要 更好地了解癌症-免疫相互作用，特别是在细胞，组织和缺陷的特定背景下 分子途径参与。人肝细胞癌（HCC），一种肝脏的原发性恶性肿瘤， 全世界癌症死亡率的第二大原因是炎症诱发的癌症的例子。 慢性病毒性肝炎、代谢性肝病和酒精滥用引起慢性炎症， 纤维化肝硬化和癌症巨噬细胞在炎症的启动和维持中的功能， 纤维化和肿瘤相关巨噬细胞（TAM）在癌症进展过程中起关键作用。但 巨噬细胞与肿瘤前病变之间相互作用的细胞和分子机制 肿瘤细胞仍然是未知的。河马信号通路最近成为一个主要的 肿瘤抑制通路，并在抑制肝细胞增殖、存活和HCC形成中发挥关键作用。 Hippo途径的中心是通过激酶级联抑制雅普/Taz转录因子，所述激酶级联起始于 Hippo激酶，在哺乳动物中为Mst 1和Mst 2。随着巨噬细胞浸润的急剧增加 在肝细胞中去除了Mst 1和Mst 2的肝脏中，本提案的目标是确定先前的 肝细胞中Hippo信号转导通过以下途径减弱肝癌发生的未知功能机制： 抑制巨噬细胞浸润和TAM分化。我们的初步研究已经确定 肝细胞中Hippo信号传导的两种分泌效应物，单核细胞趋化蛋白1（Mcp 1或Ccl 2） 和Jagged 1（Jag 1），其各自部分介导Hippo在限制炎症反应和肿瘤中的作用 增长我们假设Hippo信号在肝细胞中的一个以前未知的功能是调节 通过至少部分地抑制Mcp 1和Jag 1表达来增强促肿瘤免疫应答。具体目标1： 确定由Hippo信号调节的TAM分化的分子机制， 肝细胞在具体目标2中，我们将确定巨噬细胞在肿瘤发生中的功能。 肝细胞特异性Mst 1/2 DKO、Mst 1/2/Mcp 1 TKO和Mst 1/2/Jag 1 TKO肝脏。在具体目标3中，我们 确定肝细胞中Hippo信号传导抑制Mcp 1和其他 因素从拟议的研究中获得的知识将为进一步研究奠定坚实的新基础。 肝脏Hippo信号在诱导炎症、肿瘤微环境中的机制研究 重塑并提供新的靶点和治疗HCC的策略。

Summary Recent studies have expanded the concept that inflammation is a critical component of tumor progression. It is now clear that the tumor microenvironment largely orchestrated by inflammatory cells, is an indispensable participant in neoplastic process, fostering proliferation, survival and migration. In the last few decades, immunotherapy has become increasingly important in treating cancer. Therefore, there is an urgent need to better understand cancer-immune interactions, particular under specific contexts of cells, tissues and deficient molecular pathways involved. Human hepatocellular carcinoma (HCC), a primary malignancy of the liver and the second-leading cause of cancer mortality worldwide is an example of inflammation-induced cancer. Chronic viral hepatitis, metabolic liver diseases, and alcohol abuse cause chronic inflammation, which induces fibrosis, cirrhosis, and cancer. Macrophages function in the initiation and maintenance of inflammation and fibrosis and tumor associated macrophages (TAMs) play critical roles during cancer progression. However, the cellular and molecular mechanisms underlying reciprocal interaction between macrophages and pre-tumor/ tumor cells remain largely unknown. The Hippo signaling pathway has recently emerged as a major oncosuppressive pathway and play critical roles inhibiting hepatocyte proliferation, survival and HCC formation. Central to the Hippo pathway is the inhibition of Yap/Taz transcription factors by a kinase cascade starting from the Hippo kinase, which are Mst1 and Mst2 in mammals. As macrophage infiltration is dramatically increased in livers with Mst1 and Mst2 removed in hepatocytes, the goal of this proposal is to determine a previously unknown functional mechanism by which Hippo signaling in hepatocytes attenuates hepatocarcinogenesis by inhibiting macrophage infiltration and TAM differentiation. Our preliminary studies have led to the identification of two secreted effectors of Hippo signaling in hepatocytes, monocyte chemoattractant protein 1(Mcp1 or Ccl2) and Jagged 1 (Jag1), that each partially mediates Hippo effects in restricting inflammatory response and tumor growth. We hypothesize that a previously unknown function of Hippo signaling in hepatocytes is to regulate pro-tumor immune response by at least partially inhibiting Mcp1 and Jag1 expression. In Specific Aim 1, we will determine the molecular mechanism underlying TAM differentiation regulated by Hippo signaling in hepatocytes. In Specific Aim 2, we will determine the functions of macrophages in tumorigenesis in the hepatocyte specific Mst1/2 DKO, Mst1/2/Mcp1 TKO and Mst1/2/Jag1 TKO liver. In Specific Aim 3, we will determine the mechanisms whereby Hippo signaling in hepatocytes inhibits expression of Mcp1 and other factors. The knowledge gained from the proposed studies will establish a solid new foundation for further mechanistic investigation of hepatic Hippo signaling in inducing inflammation, tumor microenvironment remodeling and provide new targets and strategies to treat HCC.