Project 2: EGFR, ODC, and the Hypusome in H. pylori-induced Gastric Cancer

项目2总结 全球一半的人口感染幽门螺杆菌，幽门螺杆菌是已知的胃癌最大风险因素， 这是导致全球癌症死亡的第三大原因。受感染者的持续移民 确保幽门螺杆菌感染仍将是美国的主要疾病负担。抗生素不统一 根除感染，对癌症风险只有温和的影响。幽门螺杆菌诱导的癌症发生 由慢性活动性胃炎驱动。项目2将阐明导致胃炎的新机制。 和下游致癌，并将这些结果转化为人类。在颁奖期内，我们 与其他项目和核心合作，解决为什么宿主免疫反应未能消除 病原体，相反，会导致胃炎和癌症。主要发现包括：1)表皮生长因子 慢性胃炎时胃上皮细胞受体(EGFR)活化(磷酸化) 和肠化生，而胃巨噬细胞的pEGFR从胃炎到胃炎的终点升高。 癌症；2)EGFR信号调节巨噬细胞激活模式：我们用髓系生成的小鼠- EGFR的特异性缺失显示M1巨噬细胞反应、MyD88、MAPK1/3和 核因子-κB激活，趋化因子表达，Th1和Th17应答，但增强Treg应答；3) EGFR抑制剂吉非替尼减少幽门螺杆菌感染的INS-GAS小鼠或沙土鼠的胃癌；4)抑制 鸟氨酸脱羧酶(ODC)，多胺合成的限速酶，在 沙土鼠和我们建立的髓系特异性ODC缺失的小鼠的M1巨噬细胞数量增加 对幽门螺杆菌的反应和减少的定植；这是由于消除了 多胺腐胺，通过组蛋白修饰阻止转录；5)形成亚硫氨酸 幽门螺杆菌上调脱氧亚精氨酸合酶(DHPS)合成的多胺亚精胺，导致 靶向翻译巨噬细胞中编码促炎蛋白的mRNAs，构成 6)EGFR信号与幽门螺杆菌感染期间的ODC水平有关， 为催眠提供底物。这些洞察力揭示了以前未知的巨噬细胞在 胃癌的发生。我们的假设是，EGFR、ODC和Shousination形成了一个相互关联的轴 胃巨噬细胞导致幽门螺杆菌诱导的免疫失调、炎症和胃 癌症。我们将受益于此PPG中的紧密集成，以实现我们的目标，即确定 幽门螺杆菌诱导的炎症相关胃癌发生过程中的作用：1)表皮生长因子受体 激活和下游信号转导；2)ODC；3)Hypusination/DHPs。这将通过CELL- 小鼠和沙土鼠癌症模型中的特定基因缺失和抑制物，并在人类组织中得到验证； 蛋白质组学/磷蛋白质组学、代谢组学和有机模型的创新应用。我们将打破新的 关于巨噬细胞在胃癌发生中的基础，导致了新的化学预防方法。

PROJECT 2 SUMMARY Half of the global population harbors H. pylori infection, the strongest known risk factor for gastric cancer, which is the third leading cause of cancer deaths worldwide. Continued immigration of infected persons ensures that H. pylori infection will remain a major disease burden in the U.S. Antibiotics do not uniformly eradicate the infection, and exert only a modest effect on cancer risk. H. pylori-induced cancer development is driven by chronic active gastritis. Project 2 will elucidate novel mechanisms underlying gastric inflammation and downstream carcinogenesis, and will translate these results to humans. During the award period we collaborated with the other Projects and the Cores to address why the host immune response fails to eliminate the pathogen, and, instead, causes gastritis and cancer. Key discoveries included: 1) Epidermal growth factor receptor (EGFR) activation (phosphorylation) occurs in gastric epithelial cells (GECs) during chronic gastritis and intestinal metaplasia, while pEGFR in gastric macrophages is elevated from gastritis to the endpoint of cancer; 2) EGFR signaling regulates macrophage activation patterns: mice that we generated with myeloid- specific deletion of Egfr exhibited marked attenuation of M1 macrophage responses, MyD88, MAPK1/3, and NF-κB activation, chemokine expression, and Th1 and Th17 responses, but enhanced Treg response; 3) The EGFR inhibitor, gefitinib, reduces gastric cancer in H. pylori-infected INS-GAS mice or gerbils; 4) Inhibition of ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine synthesis, blocks gastric cancer in gerbils, and mice we generated with myeloid-specific deletion of Odc had increased M1 macrophage responses to H. pylori and reduced colonization; this was due to elimination of immunosuppressive effects of the polyamine putrescine, which blocks transcription through histone modifications; 5) Formation of hypusine from the polyamine spermidine by deoxyhypusine synthase (DHPS) is upregulated by H. pylori and leads to targeted translation of mRNAs encoding for pro-inflammatory proteins specifically in macrophages, constituting what we have termed “The Hypusome”; 6) EGFR signaling is linked to ODC levels during H. pylori infection, providing substrate for hypusination. These insights reveal previously unknown effects of macrophages in gastric carcinogenesis. Our hypothesis is that EGFR, ODC, and hypusination form an inter-related axis in gastric macrophages that leads to H. pylori-induced immune dysregulation, inflammation, and gastric carcinoma. We will benefit from the tight integration in this PPG to address our Aims, which are to determine the role of the following in H. pylori-induced inflammation-associated gastric carcinogenesis: 1) EGFR activation and downstream signaling; 2) ODC; 3) Hypusination/DHPS. This will be accomplished with cell- specific gene deletion and inhibitors in mouse and gerbil cancer models with validation in human tissues, and innovative use of proteomics/phosphoproteomics, metabolomics, and organoid models. We will break new ground regarding macrophages in gastric carcinogenesis, leading to novel chemoprevention approaches.