Biological Indicators of Racial Disparity in Ameloblastoma Recurrence

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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.