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Cancer Res. 2016 Jan 15;76(2):358-69. doi: 10.1158/0008-5472.CAN-15-1879. Epub 2015 Nov 17.

SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression.

Author information

1
Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan. mastanak@med.akita-u.ac.jp.
2
Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan. Department of Molecular Microbiology and Immunology, Nagasaki University School of Medicine, Nagasaki, Japan.
3
Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
4
Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, Akita, Japan.

Abstract

Tumor-associated macrophages (TAM) play complex and pivotal roles during cancer progression. A subset of metastasis-associated macrophages accumulates within metastatic sites to promote the invasion and growth of tumor cells. Src kinase-associated phosphoprotein 2 (SKAP2), a substrate of Src family kinases, is highly expressed in macrophages from various tumors, but its contribution to the tumor-promoting behavior of TAMs is unknown. Here, we report that SKAP2 regulates podosome formation in macrophages to promote tumor invasion and metastasis. SKAP2 physically interacted with Wiskott-Aldrich syndrome protein (WASP) and localized to podosomes, which were rarely observed in SKAP2-null macrophages. The invasion of peritoneal macrophages derived from SKAP2-null mice was significantly reduced compared with wild-type macrophages, but could be rescued by the restoration of functional SKAP2 containing an intact tyrosine phosphorylation site and the ability to interact with WASP. Furthermore, SKAP2-null mice inoculated with lung cancer cells exhibited markedly decreased lung metastases characterized by reduced macrophage infiltration compared with wild-type mice. Moreover, intravenously injected SKAP2-null macrophages failed to efficiently infiltrate established tumors and promote their growth. Taken together, these findings reveal a novel mechanism by which macrophages assemble the appropriate motile machinery to infiltrate tumors and promote disease progression, and implicate SKAP2 as an attractive candidate for therapeutically targeting TAMs.

PMID:
26577701
DOI:
10.1158/0008-5472.CAN-15-1879
[Indexed for MEDLINE]
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