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ResearchIn-Press PreviewBone Biology Open Access | 10.1172/JCI157340

The microbiome restrains melanoma bone growth by promoting intestinal NK and Th1 cells homing to bone

Subhashis Pal,1 Daniel S. Perrien,2 Tetsuya Yumoto,3 Roberta Faccio,4 Andreea Stoica,1 Jonathan Adams,1 Craig M. Coopersmith,6 Rheinallt M. Jones,7 M. Neale Weitzmann,1 and Roberto Pacifici1

1Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

2Division of Endocrinology Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

3Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America

4Department of Orthopedics, Washington University School of Medicine, St Louis, United States of America

5Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atkanta, United States of America

6Emory Microbiome Research Center, Emory University School of Medicine, Atlanta, United States of America

7Department of Pediatrics, Emory University School of Medicine, Atlanta, United States of America

Find articles by Pal, S. in: JCI | PubMed | Google Scholar |

1Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

2Division of Endocrinology Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

3Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America

4Department of Orthopedics, Washington University School of Medicine, St Louis, United States of America

5Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atkanta, United States of America

6Emory Microbiome Research Center, Emory University School of Medicine, Atlanta, United States of America

7Department of Pediatrics, Emory University School of Medicine, Atlanta, United States of America

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1Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

2Division of Endocrinology Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

3Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America

4Department of Orthopedics, Washington University School of Medicine, St Louis, United States of America

5Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atkanta, United States of America

6Emory Microbiome Research Center, Emory University School of Medicine, Atlanta, United States of America

7Department of Pediatrics, Emory University School of Medicine, Atlanta, United States of America

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1Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

2Division of Endocrinology Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

3Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America

4Department of Orthopedics, Washington University School of Medicine, St Louis, United States of America

5Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atkanta, United States of America

6Emory Microbiome Research Center, Emory University School of Medicine, Atlanta, United States of America

7Department of Pediatrics, Emory University School of Medicine, Atlanta, United States of America

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1Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

2Division of Endocrinology Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

3Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America

4Department of Orthopedics, Washington University School of Medicine, St Louis, United States of America

5Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atkanta, United States of America

6Emory Microbiome Research Center, Emory University School of Medicine, Atlanta, United States of America

7Department of Pediatrics, Emory University School of Medicine, Atlanta, United States of America

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1Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

2Division of Endocrinology Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

3Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America

4Department of Orthopedics, Washington University School of Medicine, St Louis, United States of America

5Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atkanta, United States of America

6Emory Microbiome Research Center, Emory University School of Medicine, Atlanta, United States of America

7Department of Pediatrics, Emory University School of Medicine, Atlanta, United States of America

Find articles by Adams, J. in: JCI | PubMed | Google Scholar

1Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

2Division of Endocrinology Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

3Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America

4Department of Orthopedics, Washington University School of Medicine, St Louis, United States of America

5Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atkanta, United States of America

6Emory Microbiome Research Center, Emory University School of Medicine, Atlanta, United States of America

7Department of Pediatrics, Emory University School of Medicine, Atlanta, United States of America

Find articles by Coopersmith, C. in: JCI | PubMed | Google Scholar

1Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

2Division of Endocrinology Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

3Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America

4Department of Orthopedics, Washington University School of Medicine, St Louis, United States of America

5Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atkanta, United States of America

6Emory Microbiome Research Center, Emory University School of Medicine, Atlanta, United States of America

7Department of Pediatrics, Emory University School of Medicine, Atlanta, United States of America

Find articles by Jones, R. in: JCI | PubMed | Google Scholar |

1Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

2Division of Endocrinology Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

3Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America

4Department of Orthopedics, Washington University School of Medicine, St Louis, United States of America

5Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atkanta, United States of America

6Emory Microbiome Research Center, Emory University School of Medicine, Atlanta, United States of America

7Department of Pediatrics, Emory University School of Medicine, Atlanta, United States of America

Find articles by Weitzmann, M. in: JCI | PubMed | Google Scholar |

1Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

2Division of Endocrinology Metabolism and Lipids, Emory University School of Medicine, Atlanta, United States of America

3Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America

4Department of Orthopedics, Washington University School of Medicine, St Louis, United States of America

5Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atkanta, United States of America

6Emory Microbiome Research Center, Emory University School of Medicine, Atlanta, United States of America

7Department of Pediatrics, Emory University School of Medicine, Atlanta, United States of America

Find articles by Pacifici, R. in: JCI | PubMed | Google Scholar

Published May 3, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI157340.
Copyright © 2022, Pal et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 3, 2022 - Version history
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Abstract

Bone metastases are frequent complications of malignant melanoma leading to reduced quality of life and significant morbidity. Regulation of immune cells by the gut microbiome influences cancer progression, but the role of the microbiome in tumor growth in bone is unknown. Using intracardiac or intratibial injections of B16-F10 melanoma cells in mice we showed that gut microbiome depletion by broad-spectrum antibiotics accelerated intraosseous tumor growth and osteolysis. Microbiome depletion blunted melanoma-induced expansion of intestinal natural killer (NK) cells and T helper 1 (Th1) cells and their migration from the gut to tumor bearing bones. Demonstrating the functional relevance of immune cell trafficking from the gut to the bone marrow (BM) in bone metastasis, blockade of S1P-mediated NK and Th1 cells intestinal egress, or inhibition of their CXCR3/CXCL9-mediated influx into the BM prevented expansion of BM NK and Th1 cells and accelerated tumor growth and osteolysis. Using a mouse model, this study revealed mechanisms of microbiota-mediated gut-bone crosstalk that are relevant to the immunological restraint of melanoma metastasis and tumor growth in bone. Microbiome modifications induced by antibiotics might have negative clinical consequences in melanoma patients.

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graphical abstract
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Version history
  • Version 1 (May 3, 2022): In-Press Preview
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