Characterization Of A Mouse Model Of Leptomeningeal Melanocytic Disease.

Abstract Melanocytic tumors in the central nervous system consist of metastatic melanoma and the more unusual primary lesions, which arise from melanocytes of the leptomeninges. Leptomeningeal melanocytic lesions include melanocytomas, diffuse melanosis and primary melanomas. Their differential diagnosis is challenging and the underlying molecular mechanisms for their generation and maintenance remain poorly characterized. The development and characterization of mouse models that parallel the human phenotype are critical for the understanding of the basic mechanisms underlying the pathology of the disease and for the pre-clinical evaluation of therapeutic strategies. We have identified glutamate signaling via the metabotropic glutamate receptor 1 (Grm1) as one key component of leptomeningeal disease. GRM1 is a member of the group I of GRMs that when bound to its ligand glutamate, couples with G alpha-q/11 (Gαq/11) to activate MEK/ERK and AKT/mTOR pathways, which are relevant downstream targets of GRM1 for melanocyte transformation. Transgenic mice TG(Grm1)EPv that express Grm1 under the regulation of the melanocyte specific promoter Dopachrome tautomerase (TG(Grm1)EPv) developed highly pigmented cutaneous melanocytic lesions located in the tail and pinnae at around 8 months of age with no apparent metastases to distant organs. Brains and spinal cords from transgenic animals of varying ages (n=15) were processed for histology and immunofluorescence. Melanosis was encountered in all animals in the leptomeninges associated to the olfactory bulb and forebrain. The other areas in which most animals displayed high levels of melanosis were the choroid plexus, cerebellopontine angle, and the lumbar spine in association with the perineurium of the nerves. Tyrosinase-related protein 1 (Trp1) positive cells were present in areas of melanosis and overlapped with high levels of Gαq/11 expression. Vimentin, known to be positive in melanocytomas but not in melanoma, was observed in the melanosis areas. Surprisingly, AKT and mTOR were not detected by immunostaining in the melanosis areas. Western blot analysis of the meninges with melanosis (n=3) showed significant elevated levels of p-ERK when compared to tissues from non-transgenic animals. A similar trend of elevated levels of expression was observed for Gαq/11, AKT, and mTOR. These observations indicate that the ectopic expression of Grm1 in melanocytes drive the formation of leptomeningeal melanocytic lesions and that the Tg(Grm1) mouse can be used for further studies aimed at understanding the mechanistic basis of leptomeningeal melanocytoma and other leptomeningeal diseases. Citation Format: Israel Castillo Gonzalez, Juliano Freitas, Xiaoshuang Li, Martina Cavallini, Lidia Kos. Characterization of a mouse model of leptomeningeal melanocytic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2916.