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

Menée in vivo et in vitro sur des modèles de cancer colorectal, cette étude met en évidence des mécanismes par lesquels, en régulant la polarisation des macrophages, la protéine MK2 favorise la tumorigenèse et l'angiogenèse tumorale

Résumé en anglais

Colon cancer is the third most common cancer type and the second leading cause of cancer-related death. Chronic inflammation is a major contributor to colon cancer development and progression, but the molecular details of how inflammation contributes to colon cancer remain unclear. The p38MAPK/MAPKAP Kinase 2 (MK2) pathway is a central mediator of cell stress and inflammation. Here, we examine the importance of this pathway in an inflammation-driven model of colon cancer using whole-body and tissue-specific MK2 knockouts, in combination with measurements of macrophage polarization, endothelial proliferation, and morphogenesis. We demonstrate that the MK2 pathway promotes colon tumor development by regulating the polarization of macrophages into an M2 tumor-promoting state that modulates the tumor microenvironment and enhances 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 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.