Departmental Papers (Dental)

Document Type

Journal Article

Date of this Version

5-1-2020

Publication Source

Cell Death and Disease

Volume

11

Issue

5

Start Page

Article number 338

DOI

10.1038/s41419-020-2560-7

Abstract

Ameloblastoma (AM) is a benign but locally aggressive tumor with high recurrences. Currently, underlying pathophysiology remains elusive, and radical surgery remains the most definitive treatment with severe morbidities. We have recently reported that AM harbors a subpopulation of tumor epithelial stem-like cells (AM-EpiSCs). Herein, we explored whether LGR5+ epithelial cells in AM possess stem-like cell properties and their potential contribution to pathogenesis and recurrence of AM. We found that LGR5 and stem cell-related genes were co-expressed in a subpopulation of AM epithelial cells both in vivo and in vitro, which were enriched under 3D-spheroid culture. As compared to LGR5− counterparts, LGR5+ AM epithelial cells showed increased expression of various EMT- and stemness-related genes, and functionally, exhibited increased capacity to form 3D-spheroids and generate human tumor 3D organoids, which recapitulated the histopathologic features of distinct subtypes of solid AM, thus, contributing a useful human tumor platform for targeted therapeutic screening. Treatment with a selective BRAFV600E inhibitor, vemurafenib, unexpectedly enriched the subpopulation of LGR5+ AM-EpiSCs in tumor 3D organoids, which may have explained therapeutic resistances and recurrences. 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 nonsurgical adjuvant therapeutic approach for this aggressively benign jaw tumor. © 2020, The Author(s).

Keywords

Ameloblastoma, Animals, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Cell Self Renewal, Drug Resistance, Neoplasm, Epithelial Cells, Epithelial-Mesenchymal Transition, Male, Mice, Nude, Neoplastic Stem Cells, Organoids, Phenotype, Proto-Oncogene Proteins B-raf, Receptors, G-Protein-Coupled, Spheroids, Cellular, Thrombospondins, vemurafenib, B Raf kinase, BRAF protein, human, G protein coupled receptor, LGR5 protein, human, thrombospondin, ameloblastoma, animal experiment, animal model, Article, cancer stem cell, cell subpopulation, controlled study, epithelial cell line, epithelial mesenchymal transition, epithelium cell, epithelium tumor, female, gene expression, histopathology, human, human cell, human tissue, in vitro study, in vivo study, Lgr5+ stem cell line, male, mouse, nonhuman, organoid, pathogenesis, priority journal, tumor model, tumor recurrence, tumor spheroid, ameloblastoma, animal, cancer stem cell, carcinogenesis, cell proliferation, cell self-renewal, drug resistance, metabolism, multicellular spheroid, nude mouse, pathology, phenotype, tumor cell line

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Date Posted: 10 February 2023

This document has been peer reviewed.