Abstract 2284: Generation and characterization of a mouse model of CRTC1-MAML2-induced mucoepidermoid carcinoma (MEC)
Authors: Chen Zirong , Li Jian-Liang , Lin Shuibin , Pan Dinglong , Ni Wei , Cao Chunxia , Gu Yumei , Hurtado Maria Daniela , Zolotukhin Sergei , Sun Tao , Kaye Frederic , Wu Lizi 
Published: August 2015

Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy and can arise in multiple other organ sites. Currently, patients with advanced, unresectable MEC have limited therapeutic options and poor treatment outcomes. Clinical improvement has been hindered by a lack of understanding of the basic mechanisms underlying MEC development as well as suitable preclinical models. The majority of MEC tumors contain a t(11;19)(q21;p13) chromosomal translocation that results in the generation of a new fusion gene product, CRTC1-MAML2. We previously showed that the CRTC1-MAML2 fusion had a strong transcriptional co-activator activity and was capable of transforming epithelial cells in vitro, in part through co-activating the transcription factor CREB. Depletion of CRTC1-MAML2 fusion expression reduced the growth and survival of human malignant MEC cells when assayed in vitro or when propagated as xenograft tumors in vivo. These findings indicate that CRTC1-MAML2 is essential in maintaining MEC malignant phenotype and serves as a promising therapeutic target. However, whether CRTC1-MAML2 fusion has a causal role in MEC induction had not been demonstrated in vivo.

In this study, we determined the oncogenic potential of the CRTC1-MAML2 fusion in vivo by establishing a Cre-regulated CRTC1-MAML2 transgenic mouse model. Through genetic crossing with MMTV-Cre mice or direct AAV-Cre transduction to induce expression of CRTC1-MAML2 transgene in salivary glandular cells, the transgenic mice developed salivary gland tumors with typical human MEC histological characteristics. Moreover, isolated tumor cells were capable of forming subcutaneous tumors in immune-compromised hosts that again recapitulate the MEC histological feature. Transcriptome analysis revealed that mouse tumors showed differential expression of genes associated with cell growth, survival, and metastasis as well as host cell immune modulating pathways in comparison with tumor-adjacent, macroscopically normal salivary gland tissues and salivary gland tissues from fusion transgene-negative littermate controls. Importantly, CRTC1-MAML2-induced tumors showed enhanced expression of known fusion target genes in human MEC, strongly supporting that this mouse tumor model molecularly resembles human MEC. Therefore, our study offered a direct proof for an oncogenic role of CRTC1-MAML2 fusion in vivo and provided the first genetically engineered mouse model for human MEC. Using this mouse MEC model, we are currently dissecting oncogenic transformation of normal salivary gland stem cells by salisphere assays, identifying cooperative genetic alterations in MEC through whole exome sequencing, and assessing its utility as a preclinical MEC model in evaluating therapeutic strategies.

Citation Format: Zirong Chen, Jian-Liang Li, Shuibin Lin, Dinglong Pan, Wei Ni, Chunxia Cao, Yumei Gu, Maria Daniela Hurtado, Sergei Zolotukhin, Tao Sun, Frederic Kaye, Lizi Wu. Generation and characterization of a mouse model of CRTC1-MAML2-induced mucoepidermoid carcinoma (MEC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2284. doi:10.1158/1538-7445.AM2015-2284