Musicant Adele M, Billington Julia M R, Damrauer Jeffrey S, Modliszewski Jennifer L, Landuau Luane J B, Tsai Yi-Hsuan, Mehta Jay H, Powers John, Betancourt Renee, Sekhri Radhika, Padilla Ricardo J, Hernandez-Prera Juan C, Hayes D Neil, Hackman Trevor G, Gokcumen Omer, Knox Sarah M, Amelio Antonio L
Graduate Curriculum in Genetics and Molecular Biology, Biological and Biomedical Sciences Program, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA.
Oncogene. 2025 Jun 2. doi: 10.1038/s41388-025-03444-7.
Mucoepidermoid carcinoma (MEC) is the most frequently occurring salivary gland malignancy. Here, we investigated transcriptomic profiles of human fetal and adult salivary glands and MEC tumors to assess programs involved in MEC progression. Molecular and genetic analyses revealed that MEC tumors and fetal salivary glands share proliferative and developmental gene expression profiles that implicate an FGFR-p53 signaling axis in salivary MEC progression. Based on these findings, we developed a genetically engineered mouse model of advanced MEC via targeted expression of the CRTC1-MAML2 oncogene in salivary ductal cells. Specifically, CRTC1-MAML2 expression combined with p53 dysregulation in salivary ducts rewires FGF signaling to drive formation of tumors with histological and molecular features of high-grade MEC. The combined bioinformatics and mouse modeling of this study demonstrate that salivary MEC progression is underpinned by reactivation of developmental signaling programs and suggests a role for FGFR targeted therapies in the treatment of high-grade MEC.
黏液表皮样癌（MEC）是最常见的涎腺恶性肿瘤。在此，我们研究了人类胎儿和成人涎腺以及MEC肿瘤的转录组图谱，以评估参与MEC进展的程序。分子和基因分析表明，MEC肿瘤和胎儿涎腺共享增殖和发育基因表达谱，这表明FGFR-p53信号轴参与涎腺MEC的进展。基于这些发现，我们通过在涎腺导管细胞中靶向表达CRTC1-MAML2癌基因，建立了晚期MEC的基因工程小鼠模型。具体而言，CRTC1-MAML2的表达与涎腺导管中p53的失调相结合，重新连接FGF信号，以驱动具有高级别MEC组织学和分子特征的肿瘤形成。本研究结合生物信息学和小鼠模型表明，涎腺MEC的进展是由发育信号程序的重新激活所支撑的，并提示FGFR靶向治疗在高级别MEC治疗中的作用。
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