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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Lewis Lung / metabolism
  • Carcinoma, Lewis Lung / pathology
  • Cell Line, Tumor
  • Disease Progression
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / pathology
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Metastasis
  • Podosomes / genetics
  • Podosomes / metabolism
  • Podosomes / pathology*
  • RAW 264.7 Cells


  • Intracellular Signaling Peptides and Proteins
  • src kinase associated phosphoprotein 2