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: 10296299
• 负责人: Antonio Luigi Amelio
• 金额: $ 49.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296299
• 关键词: Address; Agonist; Automobile Driving; Binding; Biochemical Genetics; 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; Pharmacology; Phenotype; Population; Post-Translational Protein Processing; Prevalence; Primary Neoplasm; Process; Prognosis; Property; Recurrence; Regulation; Residual Neoplasm; Resistance; Role; Salivary; Salivary Gland Neoplasms; Sampling; Signal Pathway; Signal Transduction; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissue Microarray; Tissues; Transcription Coactivator; Transcriptional Activation; 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; pluripotency factor; programs; promoter; response; single-cell RNA sequencing; targeted treatment; tool; transcription factor; transcriptome sequencing; 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.

总结