Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

SSeCKS modulates metastasis through multiple organ- and route-specific tumor-microenvironment interactions. (#182)

Masashi Muramatsu 1 , Shin Akakura 1 , Hyun-Kyung Ko 1 , Irwin H Gelman 1
  1. Roswell Park Cancer Institute, Buffalo, NY, United States

The metastatic microenvironment is composed of a complex interaction between tumor, mural and bone marrow-derived stem cells as well as soluble factors, such as chemoattractants and ligands that trigger signaling receptors. We previously characterized a role for SSeCKS/Gravin/AKAP12 (“SSeCKS”) as a metastasis suppressor based on its ability to inhibit neovascularization in the metastatic niche through the downregulation of tumor-encoded pro-angiogenic factors such as VEGF1-2. SSeCKS, whose downregulation in many solid and liquid tumors correlates with poor prognosis and increased malignancy, encodes a scaffolding protein for multiple signaling mediators such as PKC, PKA, calmodulin, cyclins and Src, and thus, is thought to normalize proliferative and cytoskeletal signaling3-5. Here, we report an additional metastasis suppressing role for SSeCKS in host microenvironment based on the increased level of metastasis formation in the peritoneum and lung by B16F10 mouse melanoma cells in SSeCKS-null (KO) vs. WT syngeneic mice. For example, the orthotopic injection of B16F10 resulted in higher formation of spontaneous peritoneal metastases in KO hosts, whereas i.v. injection led to increased lung metastases in KO hosts. Peritoneal cell-free fluid (PF) from naïve KO mice, but not PF from WT mice, could transfer sensitivity to peritoneal metastasis formation. Protein profiling showed a large increase in chemokines and cytokines in PF from KO vs. WT mice, correlating with increased in vitro B16F10 chemotaxis to the KO-PF. KO mice also exhibited increased numbers of CD11b+ monocyte-lineage cells, known to facilitate tumor cell recruitment and survival in the metastatic niche. In contrast, SSeCKS seems to control lung metastasis following i.v. injection by modulating tumor cell attachment in the lung. Specifically, the rate of B16F10-luc-G5 colonization in the first 6h after injection was 2- to 3-fold higher in KO vs. WT hosts. Our results suggest that SSeCKS controls metastasis by modulating multiple organ- and route-specific tumor-microenvironment interactions.

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