Abstract
SSeCKS/Gravin/AKAP12 (SSeCKS) controls metastasis-associated PKC and Src signaling through direct scaffolding activity. SSeCKS is downregulated in the metastases of many human cancer types, and its forced re-expression suppresses the metastatic behavior of prostate cancer cells. SSeCKS is also downregulated in breast and prostate cancer stroma, and SSeCKS-null mice (KO) are metastasis-prone, suggesting a role in suppressing formation of the pre-metastatic niche. Here, we show that lung colonization and metastasis formation by B16F10 and SM1WT1[BrafV600E] mouse melanoma cells is 9-fold higher in syngeneic KO compared to WT hosts, although there is no difference in orthotopic tumor volumes. Although melanoma cells adhered equally to KO or WT lung fibroblasts (LF), co-injection of melanoma cells with KO (vs. WT) LF increased lung macrometastasis formation in WT hosts, marked by increased melanoma colonization at foci of leaky vasculature. Increased melanoma adhesion on KO lung endothelial cells (LEC) was facilitated by increased E-Selectin levels and by increased STAT3-regulated secretion of senescence-associated factors from KO-LF, such as Vegf. Finally, the ability of SSeCKS to attenuate IFNα-induced Stat3 activation in KO-LF required its Src-scaffolding domain. Taken together, these data suggest that SSeCKS normally suppresses metastatic colonization in the lung by attenuating the expression of Selectin adhesion proteins, which can be controlled autonomously by local endothelial cells or enhanced by senescence factors secreted by neighboring fibroblasts in a SSeCKS-regulated, Src/Stat3-dependent manner.
Highlights
The vast majority of cancer-related deaths result from metastatic outgrowths at distal sites, where the combined selection for tumor cells with increased chemotactic and invasive abilities, and the ability to adapt to new microenvironments, correlates with increased resistance to therapies that are efficacious against primary-site tumors [1]
Formation of the pre-metastatic niche is governed by a complex interplay between multiple cell types, including local endothelial cells, fibroblasts and myofibroblasts, as well as recruited immune and bone marrow-derived progenitor cells, all responding to factors secreted by distal tumor cells
Our data show that the enhanced formation of lung metastases in KO hosts is governed at the level of initial colonization irrespective of Braf status, such that the increased colonization of KO lungs at 6h post-injection is similar to the increased level of melanoma cells remaining in KO vs. WT lungs 3 days later
Summary
The vast majority of cancer-related deaths result from metastatic outgrowths at distal sites, where the combined selection for tumor cells with increased chemotactic and invasive abilities, and the ability to adapt to new microenvironments, correlates with increased resistance to therapies that are efficacious against primary-site tumors [1]. There is growing appreciation that metastasis is controlled by a crosstalk between secreted factors produced by primary-site tumor cells and cells composing pre-metastatic niches (PMN) at distal sites [2,3,4]. Tumor cells “educate” PMN cells by secreting soluble factors such as S100A8 and S100A9 [5], as well as regulatory miRNAs and proteins packaged in exosomes and vesicles [6], which facilitate the recruitment of Mac1+ myeloid [5] and VEGFR1+ bone marrow-derived hematopoietic cells [7] to lung PMN. Sensitized PMN cells increase surface expression of fibronectin, which increases colonization of myeloid and bone marrow cells via their upregulation of fibronectin-binding integrin-α4β1, and increase secretion of chemokines such as SDF-1(CXCL12), TNF-α, TGF-β, VEGF-A, CXCL12 or PLGF [2, 8] that serve as tumor www.oncotarget.com attractants. B16F10 melanoma cells ectopically expressing the P-/E-Selectin ligand, sialyl Lewis X, exhibit higher frequencies of lung metastases from orthotopic primary sites [14], whereas orthotopic tumors grown in E-Selectin-null mice showed decreased lung metastasis formation compared to WT hosts [15]
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