THE ROLE OF LGR5+ EPITHELIAL STEM-LIKE CELLS IN 3D-ORGANOID MODELING AND PATHOGENESIS OF AMELOBLASTOMA

Loading...
Thumbnail Image
Degree type
DScD (Doctor of Science in Dentistry)
Graduate group
Discipline
Subject
Ameloblastoma
LGR5
Organoid
Epithelial Stem cells
Dentistry
Oral and Maxillofacial Surgery
Funder
Grant number
License
Copyright date
Distributor
Related resources
Contributor
Abstract

Ameloblastoma (AM) is a benign yet locally aggressive tumor with high recurrences. Currently, the underlying pathophysiology remains elusive and radical surgery remains the most definitive treatment with severe morbidities. Our group first reported that AM harbors a subpopulation of tumor epithelial stem-like cells (AM-EpiSCs). Herein, this study further explored whether LGR5+ epithelial cells in AM possess unique stem-like cell properties and their potential contribution to the pathogenesis and recurrence of AM. Our findings demonstrated that LGR5 and stem cell-related genes were simultaneously expressed in a subpopulation of AM epithelial cells, both in vivo and in vitro, which were markedly enriched under the 3D-spheroid culture condition. As compared to LGR5- counterparts, LGR5+ AM epithelial cells showed increased expression of several critical genes involved in the regulation of epithelial-mesenchymal transition (EMT) and stem cell pluripotency, and functionally, exhibited enhanced capacity to form 3D-spheroids and generate human tumor 3D-organoids, which recapitulated characteristic histopathologic features of distinct subtypes of solid AM. Interestingly, AM derived mesenchymal stromal cells (AM-MSCs) and their secretomes or extracellular vesicles (EVs) significantly promoted the generation of LGR5+ AM-EpiSCs both in vitro and in vivo. Furthermore, treatment with a selective BRAFV600E inhibitor, Vemurafenib, unexpectedly enriched the proportion of LGR5+ AM-EpiSCs in AM 3D-organoids, which may explain the therapeutic resistant and recurrent properties of AM conferred by this unique subpopulation of AM-EpiSCs. Therefore, the tumor 3D-organoids generated by LGR5+ AM-EpiSCs provided a novel ex vivo platform for mechanistic studies of human AM and high throughput screening of targeted therapeutic drugs. These findings suggest that LGR5+ AM-EpiSCs play a pivotal role in pathogenesis and progression of AM and targeted inhibition of both BRAF and LGR5 potentially serves a novel non-surgical adjuvant therapeutic approach for this benign yet aggressively destructive jaw tumor.

Advisor
Anh D. Le
Date of degree
2020-04-16
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation