title: Aberrantly activated AREG-EGFR signaling is required for the growth and survival of CRTC1-MAML2 fusion-positive mucoepidermoid carcinoma cells.
abstract: Salivary gland tumors (SGT) are a group of highly heterogeneous head and neck malignancies with widely varied clinical outcomes and no standard effective treatments. The CRTC1-MAML2 fusion oncogene, encoded by a recurring chromosomal translocation t(11;19)(q14-21;p12-13), is a frequent genetic alteration found in >50% of mucoepidermoid carcinomas (MEC), the most common malignant SGT. In this study, we aimed to define the role of the CRTC1-MAML2 oncogene in the maintenance of MEC tumor growth and to investigate critical downstream target genes and pathways for therapeutic targeting of MEC. By performing gene expression analyses and functional studies via RNA interference and pharmacological modulation, we determined the importance of the CRTC1-MAML2 fusion gene and its downstream AREG-EGFR signaling in human MEC cancer cell growth and survival in vitro and in vivo using human MEC xenograft models. We found that CRTC1-MAML2 fusion oncogene was required for the growth and survival of fusion-positive human MEC cancer cells in vitro and in vivo. The CRTC1-MAML2 oncoprotein induced the upregulation of the epidermal growth factor receptor (EGFR) ligand Amphiregulin (AREG) by co-activating the transcription factor CREB, and AREG subsequently activated EGFR signaling in an autocrine manner that promoted MEC cell growth and survival. Importantly, CRTC1-MAML2-positive MEC cells were highly sensitive to EGFR signaling inhibition. Therefore, our study revealed that aberrantly activated AREG-EGFR signaling is required for CRTC1-MAML2-positive MEC cell growth and survival, suggesting that EGFR-targeted therapies will benefit patients with advanced, unresectable CRTC1-MAML2-positive MEC.
authors: Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors: Z
authors: Z
authors: Chen
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: J
authors: J
authors: Chen
authors: Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors: Y
authors: Y
authors: Gu
authors: Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors: C
authors: C
authors: Hu
authors: Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL, USA.
authors: J-L
authors: 000000026487081X
authors: JL
authors: Li
authors: Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors: S
authors: S
authors: Lin
authors: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China.
authors: H
authors: H
authors: Shen
authors: Department of Medicine, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors: C
authors: C
authors: Cao
authors: Department of Medicine, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors: R
authors: R
authors: Gao
authors: Teaching Hospital of Fujian Medical University, Fujian Province Tumor Hospital, Fuzhou, Fujian, China.
authors: J
authors: J
authors: Li
authors: Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: P K
authors: PK
authors: Ha
authors: Department of Medicine, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors: F J
authors: FJ
authors: Kaye
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors: J D
authors: JD
authors: Griffin
authors: Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors: L
authors: L
authors: Wu
mesh_terms: D066258:Amphiregulin; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D018277:Carcinoma, Mucoepidermoid / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000068818:Cetuximab; D002880:Chromosomes, Human, Pair 11; D002888:Chromosomes, Human, Pair 19; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D014178:Translocation, Genetic
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D061067:Antibodies, Monoclonal, Humanized; C500984:CRTC1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C471297:MAML2 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D066246:ErbB Receptors; D000068818:Cetuximab