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SSeCKS/Akap12 suppresses metastatic melanoma lung colonization by attenuating Src-mediated pre-metastatic niche
Masashi Muramatsu1, Shin Akakura2, Lingqiu Gao3
1Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan.
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[Braf V600E] 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.
Insights
The scaffolding protein SSeCKS suppresses cancer metastasis by reducing the expression of adhesion molecules like E-Selectin. Loss of SSeCKS promotes melanoma lung colonization, highlighting its role in preventing pre-metastatic niche formation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- SSeCKS/Gravin/AKAP12 (SSeCKS) is a scaffolding protein regulating PKC and Src signaling.
- SSeCKS is downregulated in human cancer metastases and its absence promotes metastasis.
- SSeCKS deficiency in mice leads to increased metastasis, suggesting a role in suppressing pre-metastatic niche formation.
Purpose of the Study:
- To investigate the role of SSeCKS in melanoma lung colonization and metastasis.
- To elucidate the mechanisms by which SSeCKS influences the pre-metastatic niche.
Main Methods:
- Comparison of lung metastasis formation in SSeCKS-null (KO) versus wild-type (WT) mice using B16F10 and SM1WT1 melanoma cells.
- Assessment of melanoma cell adhesion to lung fibroblasts (LF) and lung endothelial cells (LEC).
- Analysis of E-Selectin expression, STAT3 activation, and senescence-associated factor secretion (e.g., Vegf) in KO vs. WT cells.
- Investigation of the role of SSeCKS's Src-scaffolding domain in regulating Stat3 activation.
Main Results:
- Lung colonization and metastasis were significantly higher (9-fold) in KO hosts compared to WT hosts, without affecting orthotopic tumor volume.
- Co-injection of melanoma cells with KO LF, but not WT LF, increased lung macrometastasis in WT hosts.
- Melanoma cell adhesion to KO LEC was enhanced due to increased E-Selectin levels.
- KO-LF secreted increased senescence-associated factors, including Vegf, regulated by STAT3.
- SSeCKS's Src-scaffolding domain was essential for attenuating IFNα-induced Stat3 activation in KO-LF.
Conclusions:
- SSeCKS suppresses metastatic colonization in the lung by attenuating Selectin adhesion protein expression.
- This suppression can be autonomous in endothelial cells or enhanced by fibroblast-secreted senescence factors.
- The SSeCKS-regulated mechanism involves Src/Stat3 signaling and influences pre-metastatic niche formation.
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