EOHSI

Research Areas

The main interest in my laboratory is to study the molecular mechanisms of melanoma development using a line of transgenic mice (TG-3) generated in my lab several years ago. From mapping studies, we have determined that about 70 kb of host sequences have been deleted by the insertion of the transgene. The host DNA had been deleted from a region of mouse chromosome 10 which is syntenic to the long arm of human chromosome 6. This region of human chromosome 6 has been shown to be highly rearranged in a large number of human nonfamilial malignant melanomas. A combination of techniques were used to identify intron 3 of metabotropic glutamate receptor 1 (Grm1) as the gene disrupted by the insertion of the transgene. The metabotropic glutamate receptors (mGluRs) belong to a family of seven transmembrane domain, G-protein coupled receptors (GPCRs). Expression of mGluRs is usually restricted to neuronal cells, but the signaling pathways activated by these receptors are widely distributed in both neural and non-neural cells. Mice with null mutations in Grm1 display reductions in hippocampal long term potentiation, and abnormalities of motor coordination and associative learning. In the TG-3 line, we showed that Grm1 is expressed only in ear tumors, but not normal ear as demonstrated by semi-quantitative RT-PCR, Western immunoblots, immunofluorescence and immunohistochemistry. Co-localization of Grm1 and the melanocyte-marker Tyrp-1 was detected only in tumors and not in the normal counterparts. Based on these results, a new transgenic line was generated with targeted Grm1 expression to melanocytes, by using Grm1 cDNA under the melanocyte-specific Dct (dopachrome tautomerase) promoter. Founder of Dct-Grm1 exhibited melanotic tumors on the tail at 7.5 months of age. High levels of Grm1 expression were observed in tail tumors but not in normal tail. Histopathological analysis showed these tumors to be very similar to those of TG-3. These results provide the compelling evidence suggesting the improtance of Grm1 signaling in melanocytic neoplasia.

Together with Dr. J. Goydos at CINJ, we begin to explore the potential role of the aberrant expression of Grm1 in human melanoma development and progression. Our data on human melanoma biopsy samples (7/19) showed expression of Grm1. Grm1 expression was not detected in two benign nevi and one normal skin samples. Similar analyses were also done with 18 human melanoma cell lines, 12/18 of these cell lines showed Grm1 expression, these results were confirmed by immunofluorescence. Co-localization of Grm1 and Tyrp1 (a melanocyte-specific marker) was detected only in lines that also showed Grm1 expression.

Research Highlights

• Melanoma research
• Melanoma research from bench to the clinic.

Scholarly Activities

• 2014 – present Council member of PanAmerican Society for Pigment Cell Research
• 2011 – present VA Oncology Study Section
• 2004 – present Member, NCI Special Emphasis Panel
• 2000 – present Planning and Review Committee for the Annual Retreat on Cancer Research
• 2004-2010 National Institute of Health Grant
• 2007-2012 National Institute of Health Grant
• 2009-2011 State of New Jersey Commission on Cancer Research Grant

Recent Publications

1. Fateeva, A, Chen, S. Study on the Complex Melanoma. Cancers (Basel). 2024;16 (5):. doi: 10.3390/cancers16050843. PubMed PMID:38473205 PubMed Central PMC10931287
2. Eddy, K, Gupta, K, Eddin, MN, Marinaro, C, Putta, S, Sauer, JM Jr, Chaly, A, Freeman, KB, Pelletier, JC, Fateeva, A et al.. Assessing Longitudinal Treatment Efficacies and Alterations in Molecular Markers Associated with Glutamatergic Signaling and Immune Checkpoint Inhibitors in a Spontaneous Melanoma Mouse Model. JID Innov. 2024;4 (2):100262. doi: 10.1016/j.xjidi.2024.100262. PubMed PMID:38445232 PubMed Central PMC10914525
3. Fateeva, A, Eddy, K, Chen, S. Overview of current melanoma therapies. Pigment Cell Melanoma Res. 2023; :. doi: 10.1111/pcmr.13154. PubMed PMID:38063139
4. Fateeva, A, Chen, S. Editorial: The role of immunotherapy in melanomas. Front Oncol. 2023;13 :1293040. doi: 10.3389/fonc.2023.1293040. PubMed PMID:37841439 PubMed Central PMC10569413
5. Spencer, KR, Portal, DE, Aisner, J, Stein, MN, Malhotra, J, Shih, W, Chan, N, Silk, AW, Ganesan, S, Goodin, S et al.. A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850. Oncotarget. 2023;14 :302-315. doi: 10.18632/oncotarget.28403. PubMed PMID:37036756 PubMed Central PMC10085060
6. Eddy, K, Gupta, K, Pelletier, JC, Isola, AL, Marinaro, C, Rasheed, MA, Campagnolo, J, Eddin, MN, Rossi, M, Fateeva, A et al.. A Spontaneous Melanoma Mouse Model Applicable for a Longitudinal Chemotherapy and Immunotherapy Study. J Invest Dermatol. 2023;143 (10):2007-2018.e6. doi: 10.1016/j.jid.2023.03.1664. PubMed PMID:36997110 PubMed Central PMC10524215
7. Eddy, K, Eddin, MN, Fateeva, A, Pompili, SVB, Shah, R, Doshi, S, Chen, S. Implications of a Neuronal Receptor Family, Metabotropic Glutamate Receptors, in Cancer Development and Progression. Cells. 2022;11 (18):. doi: 10.3390/cells11182857. PubMed PMID:36139432 PubMed Central PMC9496915
8. Silk, AW, Saraiya, B, Groisberg, R, Chan, N, Spencer, K, Girda, E, Shih, W, Palmeri, M, Saunders, T, Berman, RM et al.. A phase Ib dose-escalation study of troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors. Eur J Med Res. 2022;27 (1):107. doi: 10.1186/s40001-022-00732-w. PubMed PMID:35780243 PubMed Central PMC9250196
9. Eddy, K, Chen, S. Glutamatergic Signaling a Therapeutic Vulnerability in Melanoma. Cancers (Basel). 2021;13 (15):. doi: 10.3390/cancers13153874. PubMed PMID:34359771 PubMed Central PMC8345431
10. Eddy, K, Shah, R, Chen, S. Decoding Melanoma Development and Progression: Identification of Therapeutic Vulnerabilities. Front Oncol. 2020;10 :626129. doi: 10.3389/fonc.2020.626129. PubMed PMID:33614507 PubMed Central PMC7891057