Oncotarget

Research Papers:

SSeCKS/Akap12 suppresses metastatic melanoma lung colonization by attenuating Src-mediated pre-metastatic niche crosstalk

Masashi Muramatsu, Shin Akakura, Lingqiu Gao, Jennifer Peresie, Benjamin Balderman and Irwin H. Gelman _

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Oncotarget. 2018; 9:33515-33527. https://doi.org/10.18632/oncotarget.26067

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Abstract

Masashi Muramatsu1, Shin Akakura2, Lingqiu Gao3, Jennifer Peresie3, Benjamin Balderman3 and Irwin H. Gelman3

1Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan

2Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine 92618, CA, USA

3Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo 14263, NY, USA

Correspondence to:

Irwin H. Gelman, email: [email protected]

Keywords: SSeCKS/Akap12; pre-metastatic niche; melanoma; lung endothelial cells; adhesion

Received: July 25, 2018     Accepted: August 20, 2018     Published: September 11, 2018

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.


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