Biological Indicators of Racial Disparity in Ameloblastoma Recurrence

成釉细胞瘤复发的种族差异的生物学指标

基本信息

批准号：
10347638
负责人：
Sunday O Akintoye
金额：
$ 37.17万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-14 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10347638
关键词：
African American population Ameloblastoma Autophagocytosis BRAF gene Bioenergetics Biological Biological Markers Black Populations Black race CD34 gene Caucasians Cell Hypoxia Cell Line Cell Survival Cells Characteristics Clinical Colorectal Cancer Complex Cysteine-Rich Domain DNA Sequence Alteration Drosophila pros protein ENG gene Epithelial GTF2H1 gene Growth Head and Neck Neoplasms Hypoxia Hypoxia Inducible Factor Incidence Knowledge Lead MAP Kinase Gene Mediating Mesenchymal Modeling Mus Mutation Nutrient Odontogenic Tumors Oncogenes Oncogenic Operative Surgical Procedures Oxidative Stress PECAM1 gene Pathway interactions Patients Pattern Phagocytosis Phenotype Phosphotransferases Prevalence Prognostic Marker Property Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins B-raf Race Recurrence Recycling Residual state Running Sampling Signal Pathway Stress Testing Time Tissues Treatment outcome Variant angiogenesis base cancer stem cell cohort comparative density in vivo migration mortality neoplastic neoplastic cell prognostic indicator prognostic value racial disparity racial diversity racial health disparity stem-like cell survival outcome therapy resistant trafficking tumor tumor microenvironment

项目摘要

Project Summary Ameloblastoma accounts for 14% of all odontogenic tumors and African-Americans are five times more likely to develop ameloblastoma compared to Caucasians. Despite radical surgery, 10% of ameloblastomas recur and 25% of recurrent ameloblastomas occur in the black racial group. The biological determinants of ameloblastoma racial disparity are unclear and there are no specific biological markers to predict recurrence. Most ameloblastomas display genetic mutations of BRAF that encodes the serine/threonine protein kinase B-Raf, an activator of MAPK/ERK-signaling pathway. BRAF oncogenes induce the expression of key autophagic markers that include LC3, p62 and BECLIN1. High expressions of p62, ATG7 and LC3 have been identified in all variants of ameloblastoma and our in vivo mouse ameloblastoma tumor model displayed elevated LC3 and p62 levels. These suggest ameloblastoma recurrence can be attributed to autophagic cell survival mechanisms of residual invasive neoplastic odontogenic epithelium. Interplay of autophagic regulator BECNLIN1 with RUBICON [Run domain Beclin-1-interacting and cysteine-rich domain-containing protein], a component of LC3-associated phagocytosis (LAP) dysregulates autophagosomal maturation and endocytic trafficking to promote tumor migration and invasiveness. Our hypothesis is that autophagy reactivates residual invasive odontogenic epithelium by LAP-mediated entosis and recycling of bioenergetic cellular components. Our collaborative group has a relatively large cohort of ameloblastoma tissues and have generated epithelial-derived (EP-AMCs) and mesenchymal-derived (MS-AMCs) ameloblastoma cell lines from BRAF V600E+ multicystic/follicular ameloblastomas. To elucidate biological mechanisms contributing to racial disparity in Black versus White racial groups, we will determine prognostic biomarkers of ameloblastoma recurrence and assess how LC3-mediated autophagic ‘cargo’ processing orchestrate recurrence disparity. In Aim 1 we will determine whether autophagic proteins are pro-oncogenic adaptors associated with ameloblastoma racial disparity, aggressive phenotype and propensity for recurrence. In Aim 2, we will assess whether residual invasive ameloblastic epithelium survive using LAP-mediated entosis and recycling of bioenergetic cellular components. While ameloblastoma is relatively rare, understanding the interplay of two converging cytoprotective pathways in ameloblastoma growth pattern and recurrence has the potential to lead to new prognostic biomarkers and precision-guided therapies to alleviate racial disparities in BRAF+ tumors like ameloblastoma.

项目概要成釉细胞瘤占所有牙源性肿瘤的 14%，非洲裔美国人患成釉细胞瘤的可能性是其五倍与白种人相比，尽管进行了根治性手术，但仍有 10% 的成釉细胞瘤会复发并复发。 25% 的复发性成釉细胞瘤发生在黑人群体中成釉细胞瘤的生物学决定因素。种族差异尚不清楚，也没有特定的生物学标记来预测复发。成釉细胞瘤显示 BRAF 基因突变，编码丝氨酸/苏氨酸蛋白激酶 B-Raf，一种 MAPK/ERK 信号通路激活剂诱导关键自噬标记物的表达。包括 LC3、p62 和 BECLIN1 的所有变体均已鉴定出高表达的 p62、ATG7 和 LC3。成釉细胞瘤和我们的体内小鼠成釉细胞瘤肿瘤模型显示 LC3 和 p62 水平升高。这些表明成釉细胞瘤复发可归因于残留的自噬细胞存活机制自噬调节因子 BECNLIN1 与 RUBICON 的侵袭性肿瘤牙源性上皮的相互作用 [运行 Beclin-1 相互作用且富含半胱氨酸的结构域蛋白]，LC3 相关的一个组成部分吞噬作用（LAP）调节自噬体成熟和内吞运输以促进肿瘤我们的假设是自噬重新激活残留的侵袭性牙源性。我们的合作小组通过 LAP 介导的内吞和生物能细胞成分的回收来对上皮细胞进行修复。具有相对较大的成釉细胞瘤组织群，并产生了上皮源性 (EP-AMC) 和来自 BRAF V600E+ 多囊/滤泡的间充质来源 (MS-AMC) 成釉细胞瘤细胞系阐明导致黑人与白人种族差异的生物学机制。组中，我们将确定成釉细胞瘤复发的预后生物标志物并评估 LC3 介导的机制自噬“货物”处理协调复发差异在目标 1 中，我们将确定是否自噬。蛋白质是与成釉细胞瘤种族差异、侵袭性表型和相关的促癌适配器在目标 2 中，我们将使用评估残留的侵袭性成釉细胞上皮是否存活。 LAP 介导的内吞和生物能细胞成分的再循环虽然成釉细胞瘤相对罕见，了解成釉细胞瘤生长模式中两种聚合细胞保护途径的相互作用复发有可能导致新的预后生物标志物和精确引导的治疗来缓解 BRAF+肿瘤（如成釉细胞瘤）的种族差异。