PDCD10 as a novel driver for head and neck squamous cell carcinoma development

PDCD10作为头颈鳞状细胞癌发展的新型驱动因素

基本信息

批准号：
10648001
负责人：
Evgeny (Eugene) G Izumchenko
金额：
$ 24.6万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648001
关键词：
Alcohol consumption Animals Apoptosis Automobile Driving Bioinformatics Biological Markers Biology Carcinogens Cell Maintenance Cell Proliferation Cell physiology Cessation of life Chemoresistance Coupled Data Data Set Detection Development Diagnosis Disease Dysplasia Endowment Epithelium Event Evolution Exposure to Genes Genomics Head and Neck Squamous Cell Carcinoma Head and neck structure Histologic Histopathologic Grade Human Human Characteristics Human Papillomavirus Human papilloma virus infection Hyperkeratosis Incidence Knock-out Knowledge Lesion Link LoxP-flanked allele Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Mesenchymal Modeling Molecular Morbidity - disease rate Morphology Mucous Membrane Mus Oncogenes Oncogenic Oral Oral Stage Organoids Pathway interactions Patients Pattern Persons Phenotype Physiology Play Pre-Clinical Model Prevalence Prognosis Prognostic Marker Proteins Protocols documentation Quality Control Regulation Reporting Risk Risk Assessment Role Sampling Signal Pathway Signal Transduction Site Small Intestines Solid Specimen Squamous Epithelium Tamoxifen Therapeutic Therapeutic Intervention Tongue Tumor Promotion Up-Regulation Wild Type Mouse anti-cancer anti-tumor immune response beta catenin cancer stem cell carcinogenesis cell behavior cohort design drinking water effective therapy improved in vivo inhibitor insight interest longitudinal analysis longitudinal dataset malignant breast neoplasm malignant mouth neoplasm malignant oropharynx neoplasm mortality mouse model mouth squamous cell carcinoma neoplastic neoplastic cell new therapeutic target novel novel strategies oral tumorigenesis organizational structure overexpression patient prognosis pre-clinical self organization self-renewal stem cell function stem cell population stem cell self renewal stem cell survival stem cell therapy stem cells stemness targeted treatment therapeutic target tobacco products tool transcriptome sequencing transcriptomics tumor tumor progression tumorigenesis

项目摘要

Summary Oral cavity squamous cell carcinoma (OCSCC), the most common subtype of head and neck squamous cell carcinoma (HNSCC), is a devastating disease, causing substantial morbidity and mortality. Consumption of alcohol and tobacco products increases the risk of OCSCC. Prevalence of human papilloma virus (HPV) infection outside of oropharyngeal cancer is low, and its significance remains debatable. Only a handful of targeted therapies are available for patients with HPV-negative HNSCC (which include many oral cavity cancers), and the 5-year overall survival remains ~50%. While strategies are being designed to improve risk assessment, detection, and therapeutic intervention, these approaches are limited by our incomplete understanding of HNSCC biology, particularly in its early development. Thus, it is crucial to identify novel targets of therapeutic interest. PDCD10 is a multifaceted protein shown to be overexpressed in several solid malignancies. It was reported that PCDC10 regulates numerous oncogenic pathways and may contribute to tumorigenesis and chemoresistance by promoting cell proliferation, anti-apoptosis, epithelial-mesenchymal transition, and inhibiting anti-tumor immune responses. Recently it was suggested that PDCD10 is involved in regulating cancer stem cells (CSCs) maintenance in breast and lung cancers. In line with these observations, our studies suggest that PDCD10 plays an important role in promoting Wnt/β-catenin mediated stem cell maintenance in small intestines. Notably, preliminary data outlined below provide strong evidence for an equivalent role of PDCD10 in HNSCC, and suggest that upregulation of its expression is an important event in neoplastic progression, posing PDCD10 as a valuable prognostic biomarker and a potential therapeutic target. While PDCD10 is being actively studied in several preclinical settings, there is limited data on its role in head and neck tumorigenesis. In this proposal we will use in vivo and organoid based preclinical models, coupled with comprehensive bioinformatics analysis of longitudinally collected primary human specimens, to evaluate the role of PDCD10 in HNSCC evolution and driving aggressive tumor cells behavior. Our project pursues three independent Aims. Specifically: Aim 1 will use mice model with inducible Pdcd10 knockout in tongue epithelia to evaluate the ability of PDCD10 depletion to inhibit oral cancerogenesis in vivo; Aim 2 will use human OCSCC organoid models to assess the ability of PDCD10 to promote CSCs survival and self-renewal; while Aim 3 will use a unique already existing RNA-Seq dataset of longitudinally collected oral dysplastic lesions and OCSCC samples to delineate key PDCD10 dependent signaling pathways that drive malignant transformation. Given the devastating nature of HPV- HNSCC and dearth of effective treatment approaches, providing new insights into the cancer driving molecular mechanisms regulated by PDCD10 and using this knowledge for developing therapeutic approaches targeting its activity may ultimately improve patient prognosis.

概括口腔鳞状细胞癌（OCSCC），头颈部鳞状细胞最常见的亚型癌症（HNSCC）是一种毁灭性的疾病，导致大量的发病率和死亡率。酒精和烟草制品会增加人乳头状瘤病毒 (HPV) 感染的风险。口咽癌以外的癌症发生率较低，其意义仍存在争议，只有少数有针对性。 HPV 阴性 HNSCC（包括许多口腔癌）患者可以获得治疗，并且虽然正在设计改进风险评估的策略，但 5 年总体生存率仍约为 50%。检测和治疗干预，这些方法受到我们不完全理解的限制 HNSCC 生物学，特别是在其早期发展阶段，因此，确定新的治疗靶点至关重要。兴趣。 PDCD10 是一种多方面的蛋白质，据报道在多种实体恶性肿瘤中过度表达。 PCCDC10 调节多种致癌途径，可能有助于肿瘤发生和化疗耐药通过促进细胞增殖、抗凋亡、上皮间质转化、抑制抗肿瘤等作用最近有人提出 PDCD10 参与调节癌症干细胞 (CSC)。与这些观察结果一致，我们的研究表明 PDCD10 在乳腺癌和肺癌中发挥作用。值得注意的是，在促进 Wnt/β-连环蛋白介导的小肠干细胞维持中发挥重要作用。下面概述的初步数据为 PDCD10 在 HNSCC 中的同等作用提供了强有力的证据，并且表明其表达上调是肿瘤进展中的一个重要事件，将 PDCD10 视为一种有价值的预后生物标志物和潜在的治疗靶点。虽然 PDCD10 正在多个临床前环境中积极研究，但关于其在头部中的作用的数据有限。在本提案中，我们将使用基于体内和类器官的临床前模型，并结合对纵向收集的原始人类标本进行全面的生物信息学分析，以评估其作用 PDCD10 在 HNSCC 进化和驱动肿瘤细胞侵袭性行为中的作用我们的项目追求三个目标。具体来说：目标 1 将使用舌上皮细胞中可诱导 Pdcd10 敲除的小鼠模型。目标 2 将使用人类 OCSCC 来评估 PDCD10 消耗抑制体内口腔癌发生的能力；类器官模型可评估 PDCD10 促进 CSC 存活和自我更新的能力；而 Aim 3 将进行评估；使用纵向收集的口腔发育不良病变和 OCSCC 的独特现有 RNA-Seq 数据集样本来描绘驱动恶性转化的关键 PDCD10 依赖性信号通路。鉴于 HPV-HNSCC 的破坏性和有效治疗方法的缺乏，提供新的治疗方法深入了解 PDCD10 调节的癌症驱动分子机制，并将这些知识用于开发针对其活性的治疗方法可能最终改善患者的预后。