Abstract
Melanoma is the deadliest form of skin cancer with rising incidence, creating a significant health problem. We discovered increased expression of bone morphogenetic protein 6 (BMP6) in melanoma cells and tissues, and observed that BMP6 deficiency caused significantly delayed tumor onset and decelerated tumor progression in a melanoma mouse model. Moreover, we determined that BMP6 inhibits dermal mast cell recruitment and found that mast cell-derived mediators significantly reduced melanoma growth in vitro. In line with this, mast cell deficiency accelerated tumor onset and progression in a melanoma mouse model. Analysis of human melanoma tissues revealed a strong negative correlation between melanoma proliferation and mast cell infiltration. This study elucidates a novel role of BMP6-induced modulation of the tumor microenvironment.
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Acknowledgements
We thank Dr. Suzie Chen (Department of Chemical Biology, Rutgers University, Piscataway, USA) and Dr. Jürgen Becker (University Hospital Essen, Department for Dermatology and Venerology) for providing the GRM1-transgenic animals. We also thank Dr. Hans-Reimer Rodewald and Dr. Thorsten Feyerabend (Department of Immunology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany) for providing the mast cell-deficient Cre-Master mice. Furthermore, we thank Simone Hofmeister, Susanne Wallner, Eva Wacker, Ingmar Henz and Rudolf Jung for excellent technical assistance. Furthermore, we are grateful to Dr. Petra Rümmele for excellent advice in the evaluation of tissue sections.
Author contributions
DS, SL, and AKB conceived and designed the project. DS, PD, SL, and LF acquired the data. DS, SL, LF, PD, SK, SA, BE, CH, SK, and AKB analyzed and interpreted the data. DS, CH, and AKB wrote the manuscript.
Funding information
This work was supported by the German Cancer Aid, the German research Foundation (DFG, HE2458/18; BO1573, Research Training Group “RTG 1962/1”) and the Interdisciplinary Center for Clinical Research (IZKF) Erlangen (D24 (AB)).
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The authors declare that the data supporting the findings of this study are available within the article and its Supplementary Information files, or available from the authors upon reasonable request.
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Stieglitz, D., Lamm, S., Braig, S. et al. BMP6-induced modulation of the tumor micro-milieu. Oncogene 38, 609–621 (2019). https://doi.org/10.1038/s41388-018-0475-x
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DOI: https://doi.org/10.1038/s41388-018-0475-x
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