Abstract 2122: Pleiotropic effects of TMEFF2 variants in tumorigenesis

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL TMEFF2, a gene with an expression profile limited to brain and prostate, contains several biologically important signatures. It encodes a transmembrane protein with a short cytoplasmic tail containing a potential G protein activating domain. The extracellular domain (ectodomain) is shed in an ADAM17/γ-secretase dependent fashion and consists of two follistatin (FS) modules and an epidermal growth factor-like (EGF) domain. A critical role for TMEFF2 in tumorigenesis is suggested by the fact that it is upregulated in a significant fraction of primary and metastatic prostate tumors; however, its role in this disease is still unknown. TMEFF2 has been suggested to function as a tumor suppressor, while the ectodomain has been shown to promote growth. The discrepancies likely arise from the complexity of TMEFF2 function. TMEFF2 could signal as a ligand, a membrane bound receptor and/or a binding protein for growth factors. In addition, several isoforms have been described that differ in their C-terminus and probably in their ability to signal and/or being modified. One of these isoforms constitutes a soluble form of the protein similar to the ectodomain. In the present study we investigate the possibility that different forms of TMEFF2 may have different roles in tumorigenesis. Our data indicate that constitutive or induced overexpression of TMEFF2 in HEK293T or prostate epithelial RWPE1 cells reduces cell proliferation by 20-30%, inhibits anchorage independent growth by 5 fold, sensitizes the cells to apoptotic stimuli by 2-3 fold and/or decreases cell migration and invasion by 2 fold, suggesting that TMEFF2 functions as a tumor suppressor. Conversely, overexpression of the ectodomain or an isoform of TMEFF2 that lacks the G protein activating domain (TMEFF2-ΔGA), results in a tumorigenic phenotype, i.e. increase in cell proliferation, anchorage-independent growth, cellular migration and/or invasion. In all, these results suggest functionally different roles for different TMEFF2 variants. The role of the G protein activating domain is currently being investigated. Importantly, we demonstrate that there is an association between the ability of these TMEFF2 variants to bind to SARDH and modulate sarcosine levels and their ability to suppress tumorigenesis. Using co-immunoprecipitation studies and sarcosine levels analysis, we show that the full length tumor suppressor form of TMEFF2 binds to SARDH and modulates sarcosine levels. In contrast, expression of TMEFF2-ΔGA or the ectodomain fails to modulate sarcosine levels or bind to SARDH and in both cases they exhibit tumor promoting phenotypes. This suggests that the function of TMEFF2 may rely, at least in part, on its ability to modulate sarcosine metabolism. Differential expression of these isoforms provides a potential mechanism for the pleiotropic effects of TMEFF2 during prostate cancer development and progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2122. doi:10.1158/1538-7445.AM2011-2122