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Principal Investigator: Antonio Luigi Amelio
Organization: H. LEE MOFFITT CANCER CTR & RES INST
Fiscal Year: 2024
Award: $492,000
Funding agency: National Institute of Dental and Craniofacial Research
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.
Terms: <Address><Agonist><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Binding><Bio-Informatics><Biochemical><Bioinformatics><Body Tissues><CREB><CREB1><CREB1 gene><Cancer Genes><Cancer-Promoting Gene><Cancers><Causality><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Signaling><Cells><ChIP Sequencing><ChIP-seq><ChIPseq><Characteristics><Chromatin><Chromosomal dislocation><Chromosomal translocation><Custom><DNA><Data><Deoxyribonucleic Acid><Detectable Residual Disease><Development><Disease><Disease Progression><Disorder><Drug resistance><E-Box Elements><E-Box Motifs><E-Box Sequences><E-Box Sites><Enhancers><Equilibrium><Etiology><Event><Expression Signature><GEM model><GEMM model><Gel><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Gene Fusion><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Transcription><Genetic Translocation><Genetically Engineered Mouse><Gland><Growth Agents><Growth Factor><Growth Substances><Head and Neck Cancer><Head and Neck Carcinoma><Heterogeneity><Heterograft><Heterologous Transplantation><Human><Humulin R><IGF-1><IGF-I><IGF-I-SmC><Insulin><Insulin-Like Growth Factor 1><Insulin-Like Growth Factor I><Insulin-Like Somatomedin Peptide I><Intracellular Communication and Signaling><Intratumoral heterogeneity><Knowledge><Link><MLL/ELL><Maintenance><Major Groove><Malignant><Malignant - descriptor><Malignant Head and Neck Neoplasm><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Salivary Gland><Malignant neoplasm of salivary gland><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Minimal Residual Disease><Modern Man><Molecular><Molecular Interaction><Mucoepidermoid Carcinoma><Murine><Mus><NIDCR><NIDR><NIH><National Institute of Dental Research><National Institute of Dental and Craniofacial Research><National Institutes of Health><Neoplasm Metastasis><Novolin R><Oncogene Products><Oncogene Proteins><Oncogenes><Oncogenesis><Oncogenic><Oncoproteins><Optical reporter><Pathologic><Pathology><Patients><Phenotype><Population><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Prevalence><Primary Neoplasm><Primary Tumor><Process><Prognosis><Property><Protein Modification><Proteins Growth Factors><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent disease><Recurrent tumor><Regular Insulin><Regulation><Relapsed Disease><Residual Neoplasm><Residual Tumors><Resistance><Role><Salivary><Salivary Gland Cancer><Salivary Gland Neoplasms><Salivary Gland Tumor><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Somatomedin C><Technology><Testing><Therapeutic><Therapeutic Intervention><Tissue Arrays><Tissue Chip><Tissue Microarray><Tissues><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Transforming Genes><Tumor Cell><Tumor Promotion><Undifferentiated><United States><United States National Institutes of Health><Work><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><analyze gene expression><balance><balance function><biological signal transduction><cAMP Response Element-Binding Protein 1><cancer metastasis><cancer microenvironment><causation><cellular differentiation><chromatin immunoprecipitation-sequencing><chromosome dislocation><chromosome translocation><clinical diagnostics><clinical significance><clinically significant><conventional therapy><conventional treatment><customs><developmental><disease causation><driving><drug resistant><epithelial to mesenchymal transition><gain of function><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><genetic approach><genetic strategy><genetically engineered mouse model><genetically engineered murine model><head/neck cancer><heterogeneity in tumors><human disease><in vitro Assay><in vivo><innovate><innovation><innovative><intervention therapy><intra-tumoral heterogeneity><intratumor heterogeneity><knock-down><knockdown><malignancy><malignant head and neck tumor><malignant state><medical diagnostic><mouse model><murine model><neoplasm recurrence><neoplasm/cancer><neoplastic cell><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pharmacologic><pluripotency factor><programs><promoter><promotor><residual disease><resistance to Drug><resistant><resistant to Drug><response to therapy><response to treatment><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><t(11;19)><t(11;19)(q23;p13)><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapy response><tool><transcription co-activator><transcription factor><transcriptional co-activator><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><treatment response><treatment responsiveness><tumor><tumor cell metastasis><tumor heterogeneity><tumor initiation><tumor microenvironment><tumor xenograft><tumorigenesis><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model>