Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology

CRTC1-MAML2 在唾液腺粘液表皮样癌病理学中的作用

• 批准号: 10747770
• 负责人: Antonio Luigi Amelio
• 金额: $ 49.51万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-02 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747770
• 关键词: Role; CRTC1; MAML2; Salivary; Mucoepidermoid

Summary Mucoepidermoid carcinomas (MEC) are the most common type of malignant salivary gland tumor (SGT) with advanced MEC often being fatal due to resistance to conventional therapies. Despite their prevalence in salivary malignancies and occurrence in other tissues throughout the body, a thorough understanding of the key molecular events leading to their development has not been fully elucidated. In fact, the incomplete molecular characterization of SGTs was identified by the NIH/NIDCR as a major roadblock to the creation of new clinical diagnostics and therapies. Thus, a comprehensive understanding of the mechanisms driving MEC development and progression is critical to developing better therapeutic interventions. The Aims of this proposal address these significant knowledge gaps through the seamless integration of expertise, tools, and technologies, assembled by our group to investigate how coordinated regulation of two key signaling pathways by a CRTC1-MAML2 (C1/M2) fusion oncogene regulates differentiation and tumor grade in salivary MEC. The C1/M2 fusion is recognized as a key defining feature occurring in over 50% of MEC cases, which reprograms the CREB transcriptional network to drive tumorigenesis. However, in addition to CREB, our recent work and exciting Preliminary Studies now reveal that the C1/M2 oncoprotein also harbors gain-of-function properties that enable MYC binding and co-activation of the MYC transcriptional network. Mechanistically, our data reveal an etiologic role for C1/M2 in the altered cell heterogeneity associated with advanced salivary MEC, identify IGF-1 signaling as a hallmark of fusion positive MEC, and uncover antagonistic roles for C1/M2-CREB versus C1/M2-MYC in promoting differentiation or de-differentiation, respectively. Moreover, we developed and validated the first autochthonous mouse model of salivary MEC that faithfully mimics the genetic and pathologic features of human disease. Therefore, our central hypothesis states that C1/M2 influences intra- tumoral heterogeneity during salivary MEC development and progression by balancing expression of CREB and MYC transcriptional programs that control cell differentiation. To interrogate the molecular and cellular events that initiate, maintain the malignant state, and mediate response to therapy, we also developed an innovative optical reporter and mouse model that permits longitudinal characterization of tumorigenesis. In Specific Aim 1 we will establish whether IGF-1 regulation promotes MEC tumorigenesis and drug resistance. In Specific Aim 2 we will elucidate the mechanisms governing C1/M2 interactions with MYC and the functional significance of these interactions, and in Specific Aim 3 we will determine the clinical significance of regulating CREB versus MYC in relation to MEC pathology.

摘要 黏液表皮样癌(MEC)是涎腺恶性肿瘤中最常见的一种。 由于对传统疗法的抵抗，晚期MEC往往是致命的。尽管它们在 唾液恶性肿瘤和发生在全身其他组织中，彻底了解 导致它们发育的关键分子事件尚未完全阐明。事实上，不完整的 NIH/NIDCR确定SGT的分子特征是创建SGT的主要障碍 新的临床诊断和治疗方法。因此，对驱动机制有了全面的了解 微血管内皮细胞的发展和进展对于开发更好的治疗干预措施至关重要。目标 通过将专业知识、工具、 和技术，由我们的小组组装，以调查如何协调调节两个关键信号 CRTC1-MAML2(C1/M2)融合癌基因调控唾液分化和肿瘤分级的途径 MEC。C1/M2融合被认为是发生在超过50%的MEC病例中的关键定义特征， 对CREB转录网络进行重新编程以驱动肿瘤发生。然而，除了CREB，我们最近 工作和令人兴奋的初步研究现在揭示，C1/M2癌蛋白也有功能获得 能够与MYC结合并共同激活MYC转录网络的属性。从机械上讲，我们的 数据显示，在与晚期唾液MEC相关的细胞异质性改变中，C1/M2起了病因学作用。 确认IGF-1信号是融合阳性MEC的标志，并发现C1/M2-CREB的拮抗作用 与C_1/M_2-MYC相比，分别促进分化或去分化。此外，我们还开发了和 验证了第一个唾液微血管内皮细胞的原生小鼠模型，它忠实地模仿了遗传和 人类疾病的病理特征。因此，我们的中心假设是，C1/M2影响内部 唾液微血管内皮细胞发生发展过程中肿瘤的异质性 CREB和MYC转录程序控制细胞分化。去审问分子 以及启动、维持恶性状态和调节治疗反应的细胞事件，我们还 开发了一种创新的光学报告器和鼠标模型，允许纵向表征 肿瘤发生学。在特定的目标1中，我们将确定IGF-1调控是否促进MEC肿瘤的发生和发展 抗药性。在具体目标2中，我们将阐明控制C1/M2与MYC相互作用的机制 以及这些相互作用的功能意义，在特定目标3中，我们将确定临床 调节CREB和MYC在MEC病理中的意义。