Targeted inhibition of eIF5Ahpu suppresses tumor growth and M2-like TAM polarization in oral cancer

靶向抑制 eIF5Ahpu 可抑制口腔癌中的肿瘤生长和 M2 样 TAM 极化

• 批准号: 10573290
• 负责人: Anh D Le
• 金额: $ 45.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573290
• 关键词: 3-Dimensional; Amino Acids; Attenuated; BMI1 gene; Biological Process; Cell Proliferation; Cell physiology; Characteristics; Data Set; Development; Diagnosis; Down-Regulation; ES01; Enzymes; Epithelium; Genetic; Genetic Transcription; Growth; Head Cancer; Head and Neck Squamous Cell Carcinoma; Human; Immune; Immunocompetent; Immunosuppression; In Vitro; Infiltration; Lysine; Macrophage; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mesenchymal; Metabolism; Mixed Function Oxygenases; Modeling; Molecular; Morbidity - disease rate; Mus; NOTCH1 gene; Neck Cancer; Normal tissue morphology; Nude Mice; Oncogenes; Ornithine Decarboxylase; Patients; Phenotype; Play; Polyamines; Post-Translational Protein Processing; Prevention; Prognosis; Proliferating; Property; Protein Isoforms; Proteins; RNA-Binding Proteins; Recurrence; Role; Scheme; Signal Pathway; Signal Transduction; Spermidine; Spermidine Synthase; Stromal Cells; Survival Rate; T-Cell Activation; TWIST1 gene; Testing; The Cancer Genome Atlas; Therapeutic Effect; Tongue Squamous Cell Carcinoma; Translations; Tumor-associated macrophages; Up-Regulation; Western Blotting; analog; cancer cell; cancer prevention; cancer stem cell; cancer type; chemotherapy; cohort; density; deoxyhypusine monooxygenase; deoxyhypusine synthase; eIF-5A; genetic approach; hypusine; improved; in vivo; irradiation; mRNA Expression; malignant mouth neoplasm; mortality; mouth squamous cell carcinoma; new therapeutic target; novel; novel therapeutics; overexpression; paracrine; pharmacologic; polyamine oxidase; protein expression; self-renewal; translation factor; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

PROJECT SUMMARY Oral squamous cell carcinoma (OSCC) is the most common type of head & neck cancer and the 10th most frequent human malignancy worldwide. Over the last several decades, the overall survival rate of OSCC patients has stagnated between 40~55% despite some progress in diagnosis and therapy. The invasive growth or progression of OSCC relies on the aggressiveness of cancer cells and their unique microenvironment, whereby cancer stem cells (CSCs) and infiltrated tumor associated macrophages (TAMs) play pivotal roles. Previous studies have demonstrated that polyamines (PA) are commonly elevated in tumor microenvironment (TME) and have long been proven to be necessary for transformation and progression of various types of cancers. eIF5A2, an isoform of a highly conserved translational factor, is overexpressed in many types of cancer. Remarkably, spermidine-mediated eIF5A hypusination (eIF5Ahpu) that is implemented by two highly specialized enzymes, deoxyhypusine synthase (DHS/DHPS) and deoxyhypusine hydroxylase (DOHH), appears to be essential to most, if not all, of eIF5A’s biological functions, including its important role in regulating cancer cell proliferation, epithelial-mesenchymal transition (EMT), and CSC properties as well as immune cell functions, thus rationally emerging as a potential target for both therapy and prevention of cancer. Our analysis of TCGA dataset indicated an overall upregulation in the mRNA expression of eIF5A2 and several key enzymes involved in PA metabolism in HNSCC, which was confirmed by Western blot and IHC studies. Our studies showed that blocking DHPS/eIF5Ahpu remarkably inhibited proliferation and CSC properties of OSCC cells, which correlated a downregulation of TWIST1-BMI1 expression and NOTCH1/HES1 signaling. Meanwhile, we found that blocking DHPS/eIF5Ahpu robustly inhibited OSCC-induced polarization of M2-like TAMs and reversed the immunosuppressive effects conferred by OSCC-induced TAMs on T cell activation in vitro. More Importantly, we found that blocking DHPS/eIF5Ahpu dramatically retarded tumor growth and infiltration/polarization of M2-like TAM in an orthotopic syngeneic mouse tongue SCC model. Based on these compelling preliminary studies, we hypothesize that eIF5Ahpu might play a critical role in OSCC growth and progression due to its dual functions in regulating proliferation/CSC properties of OSCC cells and OSCC-induced M2-like TAM polarization. To test our hypothesis, we propose three specific aims: 1) Elucidate mechanism by which eIF5Ahpu regulates proliferation and CSC properties in OSCC; 2) Determine whether eIF5Ahpu plays a critical role in OSCC-induced polarization of M2-like TAMs; 3) Target eIF5Ahpu to suppress tumor growth and immunosuppressive TAMs in OSCC in vivo. New findings from this application might not only shed light on elucidating the function of eIF5Ahpu activation in development and progression of OSCC, but also hold promises for identifying novel therapeutic targets for treatment and prevention of OSCC.

项目摘要 口服鳞状细胞癌（OSCC）是头颈癌最常见的类型，第十大 全世界经常人类恶性肿瘤。在过去的几十年中，OSCC患者的总生存率 在40至55％的目的地之间停滞了诊断和治疗方面的进展。侵入性增长或 OSCC的进展取决于癌细胞及其独特的微环境的侵略性，从而 癌症干细胞（CSC）和浸润肿瘤相关巨噬细胞（TAMS）起关键作用。以前的 研究表明，多胺（PA）通常在肿瘤微环境（TME）和 长期以来，事实证明，对于各种类型的癌症的转化和发展是必要的。 EIF5A2， 高度保守的翻译因子的同工型在许多类型的癌症中过表达。值得注意的是 精子介导的EIF5A非胰岛（EIF5AHPU）由两种高度专业的酶实施， 脱氧蛋白酶合酶（DHS/DHP）和脱氧蛋白酶羟化酶（DOHH）似乎对大多数人来说都是必不可少的， 如果不是全部，EIF5A的生物学功能，包括其在调节癌细胞增殖中的重要作用， 上皮间质转变（EMT）和CSC特性以及免疫细胞功能，因此合理地 作为治疗和预防癌症的潜在目标。我们对TCGA数据集的分析 EIF5A2的mRNA表达和参与PA代谢的几种关键酶的总体上调 在HNSCC中，通过Western Blot和IHC研究证实。我们的研究表明，阻止 DHPS/EIF5AHPU明显抑制OSCC细胞的增殖和CSC特性，这与A相关 Twist1-BMI1表达和Notch1/Hes1信号的下调。意思是，我们发现阻止 DHPS/EIF5AHPU牢固抑制OSCC诱导的M2样TAM极化，并逆转了 OSCC诱导的TAM在体外T细胞激活中赋予的免疫抑制作用。更重要的是， 我们发现阻止DHP/EIF5AHPU极大地阻碍了M2样的肿瘤生长和浸润/偏光化 TAM在原位合成小鼠舌头SCC模型中。基于这些引人入胜的初步研究，我们 假设EIF5AHPU可能在OSCC的增长和进展中起关键作用，这是由于其双重功能 调节OSCC细胞和OSCC诱导的M2样TAM极化的增殖/CSC特性。测试我们的 假设，我们提出了三个具体目的：1）阐明EIF5AHPU调节增殖的机制 OSCC中的CSC属性； 2）确定EIF5AHPU是否在OSCC诱导的极化中起关键作用 m2状的tams; 3）靶向EIF5AHPU抑制体内OSCC的肿瘤生长和免疫抑制性TAM。 该应用程序的新发现不仅可能阐明阐明EIF5AHPU激活的功能 OSCC的开发和发展，但也持希望确定新的治疗靶标的 治疗和预防OSCC。