Regulation of tumor-supporting monocyte infiltration and macrophage polarization by tumor cell HuR

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Posttranscriptional events regulated by the mRNA binding protein HuR (human antigen R) often promote tumor malignancy. Yet, the impact of tumor HuR on the tumor microenvironment, specifically on monocytes and macrophages, remains elusive. Monocytes and macrophages represent an essential part of the tumor stroma. Upon infiltration of tumors, monocytes differentiate into macrophages and are educated to a tumor-associated macrophages (TAM) phenotype, which contributes to tumor growth. We hypothesize that the expression of HuR in tumor cells contributes to the chemoattractance of monocytes and their polarization towards TAM, thus, affecting tumor progression. To study the communication between tumor cells and monocytes/macrophages with regard to the HuR status in tumor cells we use hepatocellular carcinoma cells (HepG2) with a stable knockdown of HuR vs. cells overexpressing HuR. Culturing these cells as 3D tumor spheroids we follow infiltration of human monocytes and assess their polarization towards TAM. We aim at identifying the HuR-dependent factors that cause monocyte infiltration/polarization. To prove a cause-effect relation we attenuate the production of these factors in HepG2 cells. In addition, we characterize the molecular mechanisms of the HuR-dependent regulation of promising candidates. After verifying our results in a mouse hepatoma cell line (Hepa 1-6), we will use a syngraft model with tumor cells showing a genetically modified HuR status to test our in vitro findings in vivo. Our work increases the understanding how HuR in tumor cells contributes in shaping the tumor microenvironment, i.e. macrophage responses.