Advertisement

ResearchIn-Press PreviewImmunologyMetabolismOncology Open Access | 10.1172/jci.insight.187531

Increased fatty acid delivery by tumor endothelium promotes metastatic outgrowth

Deanna N Edwards,1 Shan Wang,1 Kelby Kane,2 Wenqiang Song,1 Laura C. Kim,2 Verra M. Ngwa,1 Yoonha Hwang,1 Kevin C. Ess,3 Mark R. Boothby,1 and Jin Chen4

1Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, United States of America

2Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, United States of America

4Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

Find articles by Edwards, D. in: JCI | PubMed | Google Scholar |

1Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, United States of America

2Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, United States of America

4Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

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

1Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, United States of America

2Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, United States of America

4Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

Find articles by Kane, K. in: JCI | PubMed | Google Scholar

1Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, United States of America

2Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, United States of America

4Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

Find articles by Song, W. in: JCI | PubMed | Google Scholar

1Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, United States of America

2Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, United States of America

4Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

Find articles by Kim, L. in: JCI | PubMed | Google Scholar

1Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, United States of America

2Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, United States of America

4Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

Find articles by Ngwa, V. in: JCI | PubMed | Google Scholar

1Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, United States of America

2Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, United States of America

4Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

Find articles by Hwang, Y. in: JCI | PubMed | Google Scholar

1Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, United States of America

2Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, United States of America

4Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

Find articles by Ess, K. in: JCI | PubMed | Google Scholar

1Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, United States of America

2Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, United States of America

4Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

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

1Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, United States of America

2Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, Denver, United States of America

4Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

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

Published April 8, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.187531.
Copyright © 2025, Edwards 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 April 8, 2025 - Version history
View PDF
Abstract

Metastatic outgrowth in distant microscopic niches requires sufficient nutrients, including fatty acids (FAs), to support tumor growth and to generate an immunosuppressive tumor microenvironment (TME). However, despite the important role of FAs in metastasis, the regulation of FA supply in metastatic niches has not been defined. In this report, we show that tumor endothelium actively promotes outgrowth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. We describe a process of transendothelial FA delivery via endosomes that requires mTORC1 activity. Thus, endothelial-specific targeted deletion of Raptor (RptorECKO), a unique component of the mTORC1 complex, significantly reduced metastatic tumor burden that was associated with improved markers of T cell cytotoxicity. Low dose everolimus that selectively inhibited endothelial mTORC1 improves immune checkpoint responses in metastatic disease models. This work reveals the importance of transendothelial nutrient delivery to the TME, highlighting a future target for therapeutic development.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View Supplemental Table 1

View Supplemental Table 6

View

Version history
  • Version 1 (April 8, 2025): In-Press Preview
Advertisement
Advertisement