MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis
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 inflammatio...
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Proceedings of the National Academy of Sciences
2018
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| Online Access: | http://hdl.handle.net/1721.1/119429 https://orcid.org/0000-0002-3719-0536 https://orcid.org/0000-0002-4223-971X https://orcid.org/0000-0002-1651-3607 https://orcid.org/0000-0003-4082-0292 https://orcid.org/0000-0002-9547-3251 |
| _version_ | 1811078886281183232 |
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| author | Haigis, Kevin M. Suarez Lopez, Lucia Kong, Yi Wen Sriram, Ganapathy Morandell, Sandra M. Merrick, Karl Andrew Hernandez, Yuliana I Yaffe, Michael B |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Haigis, Kevin M. Suarez Lopez, Lucia Kong, Yi Wen Sriram, Ganapathy Morandell, Sandra M. Merrick, Karl Andrew Hernandez, Yuliana I Yaffe, Michael B |
| author_sort | Haigis, Kevin M. |
| collection | MIT |
| description | 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 |
| first_indexed | 2024-09-23T11:06:53Z |
| format | Article |
| id | mit-1721.1/119429 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T11:06:53Z |
| publishDate | 2018 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1194292022-10-01T01:20:40Z MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis Haigis, Kevin M. Suarez Lopez, Lucia Kong, Yi Wen Sriram, Ganapathy Morandell, Sandra M. Merrick, Karl Andrew Hernandez, Yuliana I Yaffe, Michael B Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Suarez Lopez, Lucia Kong, Yi Wen Sriram, Ganapathy Morandell, Sandra M. Merrick, Karl Andrew Hernandez, Yuliana I Yaffe, Michael B 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 2018-12-04T19:02:22Z 2018-12-04T19:02:22Z 2018-04 2018-12-04T16:00:10Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/119429 Suarez-Lopez, Lucia et al. “MK2 Contributes to Tumor Progression by Promoting M2 Macrophage Polarization and Tumor Angiogenesis.” Proceedings of the National Academy of Sciences (April 16, 2018): 201722020. © 2018 National Academy of Sciences https://orcid.org/0000-0002-3719-0536 https://orcid.org/0000-0002-4223-971X https://orcid.org/0000-0002-1651-3607 https://orcid.org/0000-0003-4082-0292 https://orcid.org/0000-0002-9547-3251 http://dx.doi.org/10.1073/PNAS.1722020115 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Haigis, Kevin M. Suarez Lopez, Lucia Kong, Yi Wen Sriram, Ganapathy Morandell, Sandra M. Merrick, Karl Andrew Hernandez, Yuliana I Yaffe, Michael B MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis |
| title | MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis |
| title_full | MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis |
| title_fullStr | MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis |
| title_full_unstemmed | MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis |
| title_short | MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis |
| title_sort | mk2 contributes to tumor progression by promoting m2 macrophage polarization and tumor angiogenesis |
| url | http://hdl.handle.net/1721.1/119429 https://orcid.org/0000-0002-3719-0536 https://orcid.org/0000-0002-4223-971X https://orcid.org/0000-0002-1651-3607 https://orcid.org/0000-0003-4082-0292 https://orcid.org/0000-0002-9547-3251 |
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