title: SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression.
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.
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan. mastanak@med.akita-u.ac.jp.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: 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.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Shimamura
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Kuriyama
authors.affiliation: Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Maeda
authors.affiliation: Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Akiteru
authors.initials: A
authors.lastname: Goto
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Namiko
authors.initials: N
authors.lastname: Aiba
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D000069261:Podosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000067996:RAW 264.7 Cells
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C116431:src kinase associated phosphoprotein 2