MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis

• Main Authors: Haigis, Kevin M. (Author), Suarez Lopez, Lucia (Contributor), Kong, Yi Wen (Contributor), Sriram, Ganapathy (Contributor), Morandell, Sandra M. (Contributor), Merrick, Karl Andrew (Contributor), Hernandez, Yuliana I (Contributor), Yaffe, Michael B (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Proceedings of the National Academy of Sciences, 2018-12-04T19:02:22Z.
• Subjects: Article
• Online Access: Get fulltext

Chronic inflammation is a major risk factor for colorectal cancer. The p38/MAPKAP Kinase 2 (MK2) kinase axis controls the synthesis of proinflammatory cytokines that mediate both chronic inflammation and tumor progression. Blockade of this pathway has been previously reported to suppress inflammation and to prevent colorectal tumorigenesis in a mouse model of inflammation-driven colorectal cancer, by mechanisms that are still unclear. Here, using whole-animal and tissue-specific MK2 KO mice, we show that MK2 activity in the myeloid compartment promotes tumor progression by supporting tumor neoangiogenesis in vivo. Mechanistically, we demonstrate that MK2 promotes polarization of tumor-associated macrophages into protumorigenic, proangiogenic M2-like macrophages. We further confirmed our results in human cell lines, where MK2 chemical inhibition in macrophages impairs M2 polarization and M2 macrophage-induced angiogenesis. Together, this study provides a molecular and cellular mechanism for the protumorigenic function of MK2. Keywords: MK2, macrophage polarization, tumor angiogenesis, inflammation, colon cancer
Crohn's and Colitis Foundation of America (Research Fellowship Award 346496)
National Institutes of Health (U.S.) (Grant R01-GM104047)
National Institutes of Health (U.S.) (Grant R35- ES028374)
Starr Cancer Consortium (Award I9-A9-07)
Holloway Family Foundation
MIT Center for Precision Cancer Medicine