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

• 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
• 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

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.

项目摘要 氨基母细胞瘤占所有牙源性肿瘤的14％，非裔美国人的可能性是 与高加索人相比，发展成蛋白母细胞瘤。尽管进行了根本手术，但ameloboblastomas的10％复发和 在黑人种族组中，有25％的复发蛋白细胞瘤发生。蛋白细胞瘤的生物决定剂 种族差异尚不清楚，没有特定的生物标记可以预测复发。最多 氨基母细胞瘤显示了编码丝氨酸/苏氨酸蛋白激酶B-RAF的BRAF的基因突变，A MAPK/ERK信号途径的激活剂。 BRAF癌基因诱导关键自噬标记的表达 其中包括LC3，P62和Beclin1。 p62，atg7和lc3的高表达均已在所有变体中鉴定 绿细胞瘤和我们的体内小鼠杏仁粉肿瘤模型的LC3和p62水平升高。 这些表明杏仁细胞瘤复发可以归因于残留的自噬细胞存活机制 侵入性肿瘤性牙源性上皮。自噬调节器Becnlin1与Rubicon的相互作用[运行 域Beclin-1相互作用和富含半胱氨酸的结构域蛋白]，这是LC3相关的成分 吞噬作用（LAP）失调可自体成熟和内吞运输以促进肿瘤 移民和侵入性。我们的假设是自噬重新激活残留的侵入性牙源性 通过lap介导的ENSIS和生物能细胞成分的回收利用。我们的合作小组 具有相对较大的蛋白碱组织，并产生了上皮衍生（EP-AMC）和 来自BRAF V600E+多细节/卵泡的间充质衍生（MS-AMC）细胞系的绿细胞细胞系 ameloblastomas。阐明生物学机制导致黑人与白人种族的种族差异 组，我们将确定蛋白母细胞瘤复发的预后生物标志物，并评估LC3介导 自噬的“货物”处理协调复发差异。在AIM 1中，我们将确定是否自噬是否 蛋白质是与木质母细胞瘤种族差异，侵略性表型和 复发的倾向。在AIM 2中，我们将评估残留的侵入性成瘤上皮是否使用 LAP介导的ENSIS和生物能细胞成分的回收。虽然蛋白母细胞瘤相对较少 了解两个收敛的细胞保护途径在木材母细胞瘤生长模式和 复发有可能导致新的预后生物标志物和精确引导疗法以减轻 BRAF+肿瘤等种族分布，如熟母细胞瘤。