Abstract 1455: Novel role for the metastasis suppressor NM23-H1 in suppression of transendothelial migration toward CXCL12 gradient

Abstract Expression of the metastasis suppressor NM23-H1 is inversely correlated with the stage of tumor progression and metastasis in several leading malignancies including melanoma. Although multiple enzymatic activities and protein interactions have been described for this molecule, the precise mechanism by which NM23-H1 suppresses metastasis remains unknown. Metastasis of highly malignant cells toward their metastatic niche is facilitated by chemokine gradients which also guide specific populations of hematopoietic progenitor cells during their differentiation. One of the major homing factors for differentiating hematopoietic cells, as well as organospecific metastasis of melanoma cells is CXCL12 (SDF-1). Our previous in vivo tumor explant assays indicated that NM23-H1 suppresses dissemination of tumor cells from the primary site and their entry into or departure from circulation. Herein, we report that forced expression of NM23-H1 in the NM23-H1-deficient and highly invasive melanoma cell lines WM793 and 1205LU potently suppressed their ability to undergo transendothelial migration toward a CXCL12 gradient. Furthermore, we saw a dose-dependent increase in adhesion of NM23-H1 deficient cells to endothelia following the exposure to CXCL12, a process that was effectively blocked by forced expression of NM23-H1. We are currently investigating the molecular and signaling events triggered in melanoma models upon exposure to CXCL12 in order to determine the precise molecular mechanisms through which NM23-H1 disrupts CXCL12 mediated tumor cell dissemination. Our preliminary analysis of downstream signaling from the cognate receptor for CXCL12, CXCR4, indicate delayed kinetics of Akt phosphorylation in NM23-H1-expressing 1205LU cells as compared to their NM23-H1-deficient counterparts. Although NM23-H1 has been previously described as a negative regulator of the small GTPases Rac1 and Cdc42, their activation was unaffected by NM23-H1 status in 1205LU cells. These preliminary results suggest a novel role for NM23-H1 in regulating CXCL12 signaling in suppression of transendothelial migration, a critical step in melanoma metastasis 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 1455. doi:10.1158/1538-7445.AM2011-1455