An FGFR-p53 developmental signaling axis drives salivary cancer progression.

IF 7.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2025-06-02 DOI:10.1038/s41388-025-03444-7

Adele M Musicant, Julia M R Billington, Jeffrey S Damrauer, Jennifer L Modliszewski, Luane J B Landau, Yi-Hsuan Tsai, Jay H Mehta, John Powers, Renee Betancourt, Radhika Sekhri, Ricardo J Padilla, Juan C Hernandez-Prera, D Neil Hayes, Trevor G Hackman, Omer Gokcumen, Sarah M Knox, Antonio L Amelio

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引用次数: 0

Abstract

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.

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FGFR-p53发育信号轴驱动唾液癌进展。

黏液表皮样癌（MEC）是最常见的涎腺恶性肿瘤。在这里，我们研究了人类胎儿和成人唾液腺和MEC肿瘤的转录组学特征，以评估参与MEC进展的程序。分子和遗传分析显示，MEC肿瘤和胎儿唾液腺共享增殖和发育基因表达谱，这涉及唾液MEC进展中的FGFR-p53信号轴。基于这些发现，我们通过在唾液导管细胞中靶向表达CRTC1-MAML2癌基因，建立了一种晚期MEC的基因工程小鼠模型。具体来说，唾液管中CRTC1-MAML2的表达结合p53的失调，重新连接FGF信号，驱动具有高级别MEC组织学和分子特征的肿瘤的形成。本研究的生物信息学和小鼠模型的结合表明，唾液MEC的进展是由发育信号程序的重新激活所支撑的，并表明FGFR靶向治疗在治疗高级别MEC中的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.