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: 10615108
• 负责人: Antonio Luigi Amelio
• 金额: $ 49.96万
• 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/10615108
• 关键词: Address; Agonist; Automobile Driving; Binding; Biochemical; Bioinformatics; CREB1 gene; Cause of Death; Cell Differentiation process; Cells; ChIP-seq; Characteristics; Chromatin; Chromosomal translocation; Custom; DNA; Data; Development; Disease; Disease Progression; Drug resistance; E-Box Elements; Enhancers; Equilibrium; Etiology; Event; Gel; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Fusion; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Gland; Growth Factor; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Insulin; Insulin-Like Growth Factor I; Knowledge; Link; MLL/ELL; Maintenance; Major Groove; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of salivary gland; Mass Spectrum Analysis; Mediating; Molecular; Mucoepidermoid Carcinoma; Mus; National Institute of Dental and Craniofacial Research; Neoplasm Metastasis; Oncogenes; Oncogenic; Oncoproteins; Optical reporter; Pathologic; Pathology; Patients; Phenotype; Population; Post-Translational Protein Processing; Prevalence; Primary Neoplasm; Process; Prognosis; Property; Recurrence; Recurrent disease; Recurrent tumor; Regulation; Residual Neoplasm; Resistance; Role; Salivary; Salivary Gland Neoplasms; Sampling; Signal Pathway; Signal Transduction; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissue Microarray; Tissues; Transcription Coactivator; Tumor Promotion; Undifferentiated; United States; United States National Institutes of Health; Work; Xenograft Model; Xenograft procedure; clinical diagnostics; clinically significant; conventional therapy; epithelial to mesenchymal transition; gain of function; genetic approach; human disease; in vitro Assay; in vivo; innovation; knock-down; malignant state; mouse model; neoplastic cell; novel; novel therapeutic intervention; pharmacologic; pluripotency factor; programs; promoter; single-cell RNA sequencing; targeted treatment; tool; transcription factor; transcriptome sequencing; treatment response; tumor; tumor heterogeneity; tumor initiation; tumor microenvironment; tumor xenograft; tumorigenesis; Address; Agonist; Automobile Driving; Binding; Biochemical; Bioinformatics; CREB1 gene; Cause of Death; Cell Differentiation process; Cells; ChIP-seq; Characteristics; Chromatin; Chromosomal translocation; Custom; DNA; Data; Development; Disease; Disease Progression; Drug resistance; E-Box Elements; Enhancers; Equilibrium; Etiology; Event; Gel; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Fusion; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Gland; Growth Factor; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Insulin; Insulin-Like Growth Factor I; Knowledge; Link; MLL/ELL; Maintenance; Major Groove; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of salivary gland; Mass Spectrum Analysis; Mediating; Molecular; Mucoepidermoid Carcinoma; Mus; National Institute of Dental and Craniofacial Research; Neoplasm Metastasis; Oncogenes; Oncogenic; Oncoproteins; Optical reporter; Pathologic; Pathology; Patients; Phenotype; Population; Post-Translational Protein Processing; Prevalence; Primary Neoplasm; Process; Prognosis; Property; Recurrence; Recurrent disease; Recurrent tumor; Regulation; Residual Neoplasm; Resistance; Role; Salivary; Salivary Gland Neoplasms; Sampling; Signal Pathway; Signal Transduction; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissue Microarray; Tissues; Transcription Coactivator; Tumor Promotion; Undifferentiated; United States; United States National Institutes of Health; Work; Xenograft Model; Xenograft procedure; clinical diagnostics; clinically significant; conventional therapy; epithelial to mesenchymal transition; gain of function; genetic approach; human disease; in vitro Assay; in vivo; innovation; knock-down; malignant state; mouse model; neoplastic cell; novel; novel therapeutic intervention; pharmacologic; pluripotency factor; programs; promoter; single-cell RNA sequencing; targeted treatment; tool; transcription factor; transcriptome sequencing; treatment response; tumor; tumor heterogeneity; tumor initiation; tumor microenvironment; tumor xenograft; tumorigenesis

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.

概括 粘膜表皮类癌（MEC）是具有恶性唾液腺肿瘤（SGT）的最常见类型 由于对常规疗法的抵抗，晚期MEC通常是致命的。尽管他们的流行 唾液恶性肿瘤和整个组织中其他组织的发生，对 导致其发展的关键分子事件尚未完全阐明。实际上，不完整 NIH/NIDCR将SGTS的分子表征确定为创造的主要障碍 新的临床诊断和疗法。因此，对驱动机制的全面理解 MEC的发展和进展对于制定更好的治疗干预措施至关重要。目的 这项建议通过无缝的专业知识，工具， 和技术，由我们小组组装，以研究如何协调两个关键信号的调节 CRTC1-MAML2（C1/M2）融合癌基因的途径调节唾液的分化和肿瘤等级 MEC。 C1/M2融合被认为是在超过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。但是，除了克里布，我们最近 现在的工作和令人兴奋的初步研究表明，C1/M2癌蛋白也具有功能收益 MYC转录网络的MYC结合和共激活的属性。从机械上讲，我们的 数据揭示了C1/M2在与晚期唾液MEC相关的细胞异质性中的病因作用， 将IGF-1信号识别为融合阳性MEC的标志，并发现C1/M2-CREB的拮抗作用 与C1/M2-MYC相比，分别促进分化或脱不同。此外，我们开发了 验证了第一个忠实地模仿遗传和 人类疾病的病理特征。因此，我们的中心假设指出，C1/M2会影响内部 唾液MEC发育和进展过程中的肿瘤异质性通过平衡表达 控制细胞分化的CREB和MYC转录程序。询问分子 以及启动，维持恶性状态并介导对治疗的反应的细胞事件，我们也 开发了一种创新的光学报告基因和小鼠模型，该模型允许纵向表征 肿瘤发生。在特定目标1中，我们将确定IGF-1调节是否促进MEC肿瘤发生和 耐药性。在特定目标2中，我们将阐明管理C1/M2与MYC相互作用的机制 以及这些相互作用的功能意义，以及在特定目的3中，我们将确定临床 调节CREB与MYC相对于MEC病理学的重要性。