LGR5+ epithelial tumor stem-like cells generate a 3D-organoid model for ameloblastoma

Ting-Han Chang,Qunzhou Zhang,Jincheng Zeng,Lee Carrasco,Faizan Alawi,Rabie M Shanti,Anh D Le,Shihong Shi,Yanfang Liang

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.

Highlights

Ameloblastoma (AM) is a benign but locally aggressive epithelial tumor with a high recurrent rate in the jaw bones[1]
LGR5 was highly expressed in epithelial cells in AM tissues Initially, we explored whether LGR5 represented a putative marker for epithelial stem-like cells in AM
We examined the expression of LGR5 in a total of fifteen human AM tissues versus corresponding normal adjacent tissues (NATs), and six benign odontogenic cysts (OC)

Summary

Introduction

Ameloblastoma (AM) is a benign but locally aggressive epithelial tumor with a high recurrent rate in the jaw bones[1]. The WHO has recently updated AM into three categories, AM (solid/multicystic type), unicystic type, and peripheral/extraosseous type, among which the solid/ multicystic type accounts for around 80% of all AM cases and manifests with a high recurrence rate[2]. The ablative surgery remains the mainstay of treatment for AM, but severe morbidities associated with large jaw defects, impaired oral functions and facial esthetics that inhibitor) for treatment of AM is undergoing, but the clinical outcomes remain unknown. Cancer stem cells (CSCs), or tumor-initiating cells (TICs), have the capabilities of self-renewal and differentiation into non-CSCs to repopulate the cancer mass. CSCs play important roles in tumorigenesis, progression, Official journal of the Cell Death Differentiation Association Further studies are necessary to delineate the mechanisms underlying AM pathogenesis that may hold promises in developing new drugs as a nonsurgical adjunctive treatment of AM.

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