Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
J Dent Res. 2022 Nov;101(12):1517-1525. doi: 10.1177/00220345221100773. Epub 2022 Jun 10.
Ameloblastoma (AB) is an odontogenic tumor that arises from ameloblast-lineage cells. Although relatively uncommon and rarely metastatic, AB tumors are locally invasive and destructive to the jawbone and surrounding structures. Standard-of-care surgical resection often leads to disfigurement, and many tumors will locally recur, necessitating increasingly challenging surgeries. Recent genomic studies of AB have uncovered oncogenic driver mutations, including in the mitogen-activated protein kinase (MAPK) and Hedgehog signaling pathways. Medical therapies targeting those drivers would be a highly desirable alternative or addition to surgery; however, a paucity of existing AB cell lines has stymied clinical translation. To bridge this gap, here we report the establishment of 6 new AB cell lines-generated by "conditional reprogramming"-and their genomic characterization that reveals driver mutations in FGFR2, KRAS, NRAS, BRAF, PIK3CA, and SMO. Furthermore, in proof-of-principle studies, we use the new cell lines to investigate AB oncogene dependency and drug sensitivity. Among our findings, AB cells with KRAS or NRAS mutation (MAPK pathway) are exquisitely sensitive to MEK inhibition, which propels ameloblast differentiation. AB cells with activating SMO-L412F mutation (Hedgehog pathway) are insensitive to vismodegib; however, a distinct small-molecule SMO inhibitor, BMS-833923, significantly reduces both downstream Hedgehog signaling and tumor cell viability. The novel cell line resource enables preclinical studies and promises to speed the translation of new molecularly targeted therapies for the management of ameloblastoma and related odontogenic neoplasms.
成釉细胞瘤（AB）是一种来源于成釉细胞系的牙源性肿瘤。虽然相对少见且很少转移，但 AB 肿瘤具有局部侵袭性，会破坏颌骨和周围结构。标准的手术切除往往会导致毁容，而且许多肿瘤会局部复发，需要进行越来越具有挑战性的手术。最近对 AB 的基因组研究揭示了致癌驱动突变，包括丝裂原活化蛋白激酶（MAPK）和 Hedgehog 信号通路。针对这些驱动因素的药物治疗将是手术的理想替代或补充；然而，现有的 AB 细胞系数量不足阻碍了临床转化。为了弥补这一差距，我们在此报告了 6 种新的 AB 细胞系的建立——通过“条件重编程”生成——及其基因组特征，揭示了 FGFR2、KRAS、NRAS、BRAF、PIK3CA 和 SMO 中的驱动突变。此外，在原理验证研究中，我们使用新的细胞系来研究 AB 致癌基因依赖性和药物敏感性。我们的研究结果表明，具有 KRAS 或 NRAS 突变（MAPK 通路）的 AB 细胞对 MEK 抑制高度敏感，这促进了成釉细胞分化。具有激活 SMO-L412F 突变（Hedgehog 通路）的 AB 细胞对维莫德吉不敏感；然而，一种独特的小分子 SMO 抑制剂 BMS-833923 显著降低了下游 Hedgehog 信号和肿瘤细胞活力。新的细胞系资源使临床前研究成为可能，并有望加速针对成釉细胞瘤和相关牙源性肿瘤的新分子靶向治疗的转化。
