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

• 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
• 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

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.

总结 口腔鳞状细胞癌（OCSCC）是头颈部鳞状细胞癌中最常见的亚型， 头颈部鳞状细胞癌（HNSCC）是一种毁灭性的疾病，导致大量的发病率和死亡率。消费 酒精和烟草产品会增加OCSCC的风险。人乳头瘤病毒（HPV）感染的流行率 口咽癌以外的癌症发病率较低，其重要性仍有争议。只有少数目标 HPV阴性HNSCC（包括许多口腔癌）患者可获得治疗， 5年总生存率保持在~ 50%。虽然正在制定改进风险评估的战略， 检测和治疗干预，这些方法受到我们对 HNSCC生物学，特别是在其早期发展。因此，寻找新的治疗靶点至关重要 兴趣 PDCD 10是一种多方面的蛋白质，在几种实体恶性肿瘤中过表达。有消息称 PCDC 10调节许多致癌途径，并可能导致肿瘤发生和化疗耐药性 通过促进细胞增殖、抗凋亡、上皮-间质转化和抑制抗肿瘤 免疫反应。最近有人提出PDCD 10参与调节癌症干细胞（CSC）。 乳腺癌和肺癌的维持治疗。与这些观察结果一致，我们的研究表明，PDCD 10发挥作用， 在促进Wnt/β-catenin介导的小肠干细胞维持中起重要作用。值得注意的是， 以下概述的初步数据为PDCD 10在HNSCC中的等效作用提供了强有力的证据， 提示其表达上调是肿瘤进展中的重要事件，将PDCD 10作为 一种有价值的预后生物标志物和潜在的治疗靶点。 虽然PDCD 10正在几个临床前环境中进行积极研究，但关于其在头部疾病中的作用的数据有限。 和颈部肿瘤发生。在本提案中，我们将使用基于体内和类器官的临床前模型， 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 PDCD 10在HNSCC演变中的作用并驱动侵袭性肿瘤细胞行为。我们的项目追求三个 独立的目标。具体而言：Aim 1将使用舌上皮中具有诱导型Pdcd 10敲除的小鼠模型 评估PDCD 10耗竭抑制体内口腔癌发生的能力;目标2将使用人OCSCC 类器官模型来评估PDCD 10促进CSC存活和自我更新的能力;而Aim 3将 使用纵向收集的口腔异型增生病变和OCSCC的独特的现有RNA-Seq数据集 样本描绘关键PDCD 10依赖的信号通路，驱动恶性转化。 鉴于HPV-HNSCC的破坏性和缺乏有效的治疗方法， 深入了解PDCD 10调控的癌症驱动分子机制，并利用这些知识 开发针对其活性的治疗方法可能最终改善患者预后。