Colorectal cancer is the second leading cause of cancer mortality in the US, in part due to the lack of effective therapies for advanced disease. Thus, there is an urgent need to identify molecules/pathways involved in colon cancer development and metastasis for cancer treatment. Glutamate is an essential amino acid that plays important roles in signaling as a major neurotransmitter in mammalian central nervous system (CNS). Glutamate signaling is mediated by glutamate receptors. GRM3 is one of the group II metabotropic glutamate receptors. The glutamatergic system is mainly restricted to the CNS. However, it has been recently shown that GRM3 is frequently mutated in melanoma and that mutant GRM3 increased anchorage- independent growth and migration of melanoma cells. In addition, activation of GRM3 has been reported to sustain tumorigenic potential of glioma-initiating cells. Pharmacological blockade of GRM3 reduced growth of glioma cells in vitro and in vivo. These studies suggest that GRM3 may play a role in cancer. Our preliminary data showed that expression of GRM3 is significantly elevated in more than 90% of colon cancer specimens examined. Knockdown of GRM3 in colon cancer cells suppresses cell survival and anchorage-independent growth in vitro and inhibits tumor growth in a xenograft model in vivo. Mechanistically GRM3 inactivates protein kinase A (PKA) and activates AKT. In addition, TGF? increases GRM3 expression and that knockdown of GRM3 enhances TGF?-mediated tumor suppressor function. These studies suggest that upregulation of GRM3 expression is a functionally important molecular event during colon cancer development and progression. Therefore, GRM3 may play an important role in colon cancer tumorigenesis and metastasis and could be a potential target for colon cancer treatment. In this proposal, we will investigate the mechanisms by which TGF? regulates GRM3 expression and whether their crosstalk plays a role in colon cancer metastasis. We will also determine GRM3 function in colon cancer using genetic mouse models and whether GRM3 contributes to development and/or maintenance of colon cancer metastasis using an orthotopic mouse model. Furthermore, we will demonstrate the clinical relevance and significance of elevated GRM3 in colon cancer patient samples. The completion of these studies will identify TGF?/GRM3/PKA as a novel signaling axis regulating colon cancer development and progression and establish GRM3 as a potential therapeutic target for colon cancer treatment.