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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要口腔鳞状细胞癌 (OSCC) 是最常见的头颈癌类型，在最常见的头颈癌中排名第十。过去几十年来，全球人类恶性肿瘤频发，OSCC 患者的总体生存率有所下降。尽管诊断和治疗取得了一些进展，但侵袭性生长仍停滞在 40%~55% 之间。 OSCC的进展依赖于癌细胞的侵袭性及其独特的微环境，因此癌症干细胞（CSC）和浸润的肿瘤相关巨噬细胞（TAM）发挥着关键作用。研究表明，多胺 (PA) 在肿瘤微环境 (TME) 中普遍升高，并且长期以来已被证明对于各种类型的癌症的转化和进展是必需的，高度保守的翻译因子的同种型，在许多类型的癌症中过度表达。亚精胺介导的 eIF5A hypusination (eIF5Ahpu) 由两种高度专业化的酶实现，脱氧马尿苷合成酶 (DHS/DHPS) 和脱氧马尿苷羟化酶 (DOHH) 似乎对大多数人来说是必需的， eIF5A 的生物学功能（如果不是全部的话），包括其在调节癌细胞增殖中的重要作用，上皮间质转化 (EMT)、CSC 特性以及免疫细胞功能，从而合理地我们对 TCGA 数据集的分析表明，它正在成为癌症治疗和预防的潜在目标。 eIF5A2 和参与 PA 代谢的几种关键酶的 mRNA 表达全面上调在 HNSCC 中，蛋白质印迹和 IHC 研究证实了这一点。 DHPS/eIF5Ahpu 显着抑制 OSCC 细胞的增殖和 CSC 特性，这与同时，我们发现 TWIST1-BMI1 表达和 NOTCH1/HES1 信号传导的下调。 DHPS/eIF5Ahpu 强烈抑制 OSCC 诱导的 M2 样 TAM 极化，并逆转 OSCC 诱导的 TAM 对 T 细胞体外激活产生的免疫抑制作用。我们发现阻断 DHPS/eIF5Ahpu 可显着延缓肿瘤生长和 M2 样细胞的浸润/极化基于这些令人信服的初步研究，我们在原位同基因小鼠舌 SCC 模型中进行了 TAM。研究表明，eIF5Ahpu 可能在 OSCC 的生长和进展中发挥关键作用，因为它具有双重功能：调节 OSCC 细胞的增殖/CSC 特性和 OSCC 诱导的 M2 样 TAM 极化。假设，我们提出三个具体目标：1）阐明eIF5Ahpu调节增殖的机制和 OSCC 中的 CSC 特性；2) 确定 eIF5Ahpu 是否在 OSCC 诱导的极化中发挥关键作用 M2 样 TAM；3) 靶向 eIF5Ahpu 以抑制体内 OSCC 中的肿瘤生长和免疫抑制 TAM。该应用的新发现可能不仅有助于阐明 eIF5Ahpu 激活在口腔鳞癌的发生和进展，但也有望确定新的治疗靶点口腔鳞癌的治疗和预防。