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: 10441837
• 负责人: Anh D Le
• 金额: $ 46.93万
• 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/10441837
• 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; Epithelial; Genetic; Genetic Transcription; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Immune; Immunocompetent; Immunosuppression; In Vitro; Infiltration; Light; Lysine; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mesenchymal; Metabolism; Mixed Function Oxygenases; Modeling; Molecular; Morbidity - disease rate; Mus; NOTCH1 gene; Normal tissue morphology; Nude Mice; ODC1 gene; Oncogenes; Ornithine Decarboxylase; Patients; Pharmacology; Phenotype; Play; Polyamines; Post-Translational Protein Processing; Prevention; Prognosis; 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; base; cancer cell; cancer prevention; cancer stem cell; cancer type; chemotherapy; cohort; density; deoxyhypusine monooxygenase; deoxyhypusine synthase; genetic approach; hypusine; in vivo; irradiation; mRNA Expression; macrophage; malignant mouth neoplasm; mortality; mouth squamous cell carcinoma; new therapeutic target; novel; novel therapeutics; overexpression; paracrine; polyamine oxidase; protein expression; self-renewal; 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.

项目总结