Biological Indicators of Racial Disparity in Ameloblastoma Recurrence

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.

Grant Number: 5R01CA259307-04
NIH Institute/Center: NIH
Principal Investigator: Sunday Akintoye