Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.
Department of Oral & Maxillofacial Surgery, Penn Medicine Hospital of the University of Pennsylvania, Perelman Center for Advanced Medicine, Philadelphia, PA, USA.
Cell Death Dis. 2020 May 7;11(5):338. doi: 10.1038/s41419-020-2560-7.
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 BRAF 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.
成釉细胞瘤（AM）是一种良性但具有局部侵袭性的肿瘤，复发率高。目前，其潜在的病理生理学机制仍不清楚，根治性手术仍然是最有效的治疗方法，但会带来严重的病残率。我们最近报道 AM 中存在肿瘤上皮干细胞样细胞（AM-EpiSCs）亚群。在此，我们探讨了 AM 中的 LGR5 上皮细胞是否具有干细胞样细胞特性，以及它们对 AM 发病机制和复发的潜在贡献。我们发现，LGR5 和干细胞相关基因在体内和体外的 AM 上皮细胞的亚群中共同表达，在 3D 球体培养中富集。与 LGR5 相比，LGR5 AM 上皮细胞表现出各种 EMT 和干细胞相关基因的表达增加，并且在功能上，形成 3D 球体和生成人肿瘤 3D 类器官的能力增加，这些类器官再现了不同亚型实体 AM 的组织病理学特征，因此，为靶向治疗筛选提供了一个有用的人类肿瘤平台。用选择性 BRAF 抑制剂 vemurafenib 治疗出人意料地富集了肿瘤 3D 类器官中的 LGR5 AM-EpiSCs 亚群，这可能解释了治疗抵抗和复发的原因。这些发现表明，LGR5 AM-EpiSCs 在 AM 的发病机制和进展中起关键作用，靶向抑制 BRAF 和 LGR5 可能为这种侵袭性良性颌骨肿瘤提供一种新的非手术辅助治疗方法。
