Increased fatty acid delivery by tumor endothelium promotes metastatic outgrowth
Deanna N. Edwards, Shan Wang, Kelby Kane, Wenqiang Song, Laura C. Kim, Verra M. Ngwa, Yoonha Hwang, Kevin Ess, Mark R. Boothby, Jin Chen
Deanna N. Edwards, Shan Wang, Kelby Kane, Wenqiang Song, Laura C. Kim, Verra M. Ngwa, Yoonha Hwang, Kevin Ess, Mark R. Boothby, Jin Chen
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Research Article Immunology Metabolism Oncology

Increased fatty acid delivery by tumor endothelium promotes metastatic outgrowth

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 antitumor cytolysis by transferring FAs into developing metastatic tumors. We describe a process of transendothelial FA delivery via endosomes that requires mTORC1 activity. Thus, endothelial cell–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.

Authors

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

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Figure 4

Raptor/mTORC1 loss reduces vesicle trafficking of fatty acids in endothelial cells.

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Raptor/mTORC1 loss reduces vesicle trafficking of fatty acids in endothe...
(A and B) Gene set enrichment analysis of WT or Rptor-KO endothelial cells (n = 4 per group). (A) Top enriched pathways are shown. Normalized enrichment score (NES) and false discovery rate (FDR) q values are indicated. (B) Enrichment plots for RAB trafficking pathways are shown. (C) Immunofluorescence of RAB5 (left) or RAB7 (right) (both red) was performed on WT or Rptor-KO endothelial cells (n = 3 per group). Representative images are shown. Nuclei were stained with DAPI (blue). Scale bars: 100 μm. (D) Gene expression volcano plot from data in A and B. Differentially upregulated genes in Rptor-KO cells are displayed in red, while downregulated genes are in blue. (E) Transendothelial transport of BODIPY-C16 in WT or Rptor-KO endothelial cells transfected with siRNA against Clstn1 (n = 3 per group). BODIPY-C16 intensity in LLC tumor cells was normalized to the non-targeting control (NTC) and presented as fold change (FC). (F) LLC tumor cells were cultured in fractionated conditioned media from WT or Rptor-KO endothelial cells (n = 4 per group). *P < 0.05, **P < 0.01, ****P < 0.001 by unpaired, 2-tailed Student’s t test (C), 2-way ANOVA with Tukey’s post hoc test (E), or 2-way ANOVA with Šidák’s multiple-comparison post hoc test (F).