Metastasis Promotion: Control of the Src/STAT-Regulated Senescent Stromal Secretome by SSeCKS/AKAP12 Scaffolding Protein

There is growing appreciation that the pre-metastatic niche (pre-MN) results from crosstalk between secreted factors from primary-site tumor cells, tumor-associated macrophages (TAM), stromal and endothelial cells in the pre-MN, and myeloid precursor (BMMP) and mesenchymal stem cells (BMSC) recruited to the pre-MN from the bone marrow. Moreover, pro-oncogenic genetic changes in the pre-MN are associated with increased incidence of the senescence-associated secretory phenotype (SASP), noted for the local secretion of inflammatory mediators that promote metastasis by activating local cells and by increasing recruitment of BMMP and BMSC. The downregulation of SSeCKS/AKAP12, a scaffolding protein for PKC, Src and PKA, in stromal cells has been linked to increased incidence of cancer malignancy including metastasis. Moreover, SSeCKS deficiency induces a senescence-associated secretory phenotype (SASP) in fibroblasts, a phenomenon known to promote metastatic progression. Here, we show that B16F10-luciferase melanoma cells injected s.c. or i.v. into SSeCKS-null mice (KO) induce higher levels of peritoneal metastasis compared to WT hosts, whereas primary-site s.c. tumors grow at the same rate. The increased metastasis correlated with increased tumor cell chemotaxis, dependent on tumor cell CXCR3 and CXCL9/10 ligands secreted by KO peritoneal myofibroblasts (PMF). Increased PMF SASP was controlled by the loss of scaffolding of Src and PKCα, correlating with increased expression and secretion of CXCL9/10 induced by enhanced Src-STAT1 signaling. Our data are consistent with the notion that SSeCKS normally suppresses pre-MN formation by attenuating Src/PKCα signaling in stromal cells, thereby inhibiting SASP-induced metastatic chemotaxis and colonization of pre-MN. These data further the concept that metastatic progression can be prevented or treated by the therapeutic targeting Src-family kinases.