Role of CRTC1-MAML2 in Salivary Mucoepidermoid Carcinoma Pathobiology

总结 粘液表皮样癌（MEC）是最常见的恶性唾液腺肿瘤（SGT）类型， 晚期MEC由于对常规疗法的抗性而常常是致命的。尽管它们在 唾液恶性肿瘤和发生在其他组织在整个身体，一个彻底的了解， 导致其发展的关键分子事件尚未完全阐明。事实上，不完整 NIH/NIDCR将SGT的分子特征鉴定为创建 新的临床诊断和治疗方法。因此，全面了解驱动机制 MEC的发展和进展对于开发更好的治疗干预至关重要。目标 通过将专业知识、工具 和技术，由我们的小组组装，以研究如何协调两个关键信号的调节 CRTC 1-MAML 2（C1/M2）融合癌基因通路调节唾液腺中的分化和肿瘤分级 MEC。C1/M2融合被认为是超过50%的MEC病例中发生的关键定义特征， 重新编程CREB转录网络以驱动肿瘤发生。然而，除了CREB，我们最近的 一项令人兴奋的工作和初步研究现在揭示，C1/M2癌蛋白也具有功能获得性 使MYC结合和MYC转录网络的共激活成为可能的性质。机械地，我们 数据揭示了C1/M2在与晚期唾液MEC相关的改变的细胞异质性中的病因学作用， 鉴定IGF-1信号传导作为融合阳性MEC标志，并揭示C1/M2-CREB的拮抗作用 与C1/M2-MYC相比，分别在促进分化或去分化方面。此外，我们还开发了 验证了第一个唾液MEC的本地小鼠模型，该模型忠实地模拟了遗传和 人类疾病的病理特征。因此，我们的中心假设指出，C1/M2影响内- 在唾液MEC发展和进展过程中通过平衡 控制细胞分化的CREB和MYC转录程序。去审问那些 以及启动、维持恶性状态和介导对治疗反应的细胞事件，我们还 开发了一种创新的光学报告和小鼠模型，允许纵向表征 肿瘤发生在具体目标1中，我们将确定IGF-1调节是否促进MEC肿瘤发生， 耐药性在具体目标2中，我们将阐明C1/M2与MYC相互作用的机制 以及这些相互作用的功能意义，在具体目标3中，我们将确定临床 调节CREB相对于MYC在MEC病理学中的意义。

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.