Regulation of tumor-supporting monocyte infiltration and macrophage polarization by tumor cell HuR
Final Report Abstract
The development of a tumor is strongly influenced by its immediate microenvironment, which is shaped to a large extent by infiltrating immune cells. Macrophages have been shown to play a decisive role in tumor progression and elevated macrophage infiltrates have been correlated with bad prognosis. In the present project, we aimed at understanding how expression of the RNA-binding protein HuR in tumor cells affects their crosstalk with macrophages. To this end, HuR-depleted breast tumor cells were generated. In contrast to the generally accepted pro-tumorigenic properties of HuR, we observed enhanced macrophage infiltration into HuR-depleted 3-dimensional breast tumor spheroids. We further identified increased expression of the chemokine CCL5 in HuR-k/d cells to contribute to this phenotype. Mechanistically, HuR did not regulate CCL5 post-transcriptionally, but inhibited CCL5 transcription. Importantly, HuR also inversely correlated with CCL5 expression and macrophage infiltration in human breast tumor patients. While HuR is generally assumed to support tumor growth, reducing HuR expression therapeutically can be predicted to be less successful than hoped for due to its newly identified role in the interplay between tumor cells and macrophages. These apparently contradictory observations with respect to the role of HuR in tumor development might also explain the astonishing lack of successful HuR- targeted tumor therapeutic approaches.
Publications
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(2017) Cancer cell and macrophages cross-talk in the tumor microenvironment. Current Opinion in Pharmacology 35: 12-19
Dehne N, Mora J, Namgaladze D, Weigert A, Brüne B
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(2017) S1P provokes tumor lymphangiogenesis via macrophage-derived mediators such as IL-1β or lipocalin-2. Mediators of Inflammation
Syed SN, Jung M, Weigert A, Brüne B
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The RNA-binding protein HuR inhibits expression of CCL5 and limits recruitment of macrophages into tumors. Molecular Carcinogenesis
Brauß TF, Winslow S, Lampe S, Scholz A, Weigert A, Dehne N, von Stedingk K, Schmid T, Brüne B
