Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness
Tomofumi Ando, Ikue Tai-Nagara, Yuki Sugiura, Dai Kusumoto, Koji Okabayashi, Yasuaki Kido, Kohji Sato, Hideyuki Saya, Sutip Navankasattusas, Dean Y. Li, Makoto Suematsu, Yuko Kitagawa, Elena Seiradake, Satoru Yamagishi, Yoshiaki Kubota
Tomofumi Ando, Ikue Tai-Nagara, Yuki Sugiura, Dai Kusumoto, Koji Okabayashi, Yasuaki Kido, Kohji Sato, Hideyuki Saya, Sutip Navankasattusas, Dean Y. Li, Makoto Suematsu, Yuko Kitagawa, Elena Seiradake, Satoru Yamagishi, Yoshiaki Kubota
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Research Article Angiogenesis Vascular biology

Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness

Abstract

Blood vessel abnormalization alters cancer cell metabolism and promotes cancer dissemination and metastasis. However, the biological features of the abnormalized blood vessels that facilitate cancer progression and whether they can be targeted therapeutically have not been fully investigated. Here, we found that an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), is expressed preferentially in abnormalized vessels of advanced colorectal cancers in humans and that its expression correlates negatively with long-term survival. Endothelial cell–specific deletion of Flrt2 in mice selectively pruned abnormalized vessels, resulting in a unique metabolic state termed “oxygen-glucose uncoupling,” which suppressed tumor metastasis. Moreover, Flrt2 deletion caused an increase in the number of mature vessels, resulting in a significant increase in the antitumor effects of immune checkpoint blockers. Mechanistically, we found that FLRT2 forms noncanonical interendothelial adhesions that safeguard against oxidative stress through homophilic binding. Together, our results demonstrated the existence of tumor-specific interendothelial adhesions that enable abnormalized vessels to facilitate cancer aggressiveness. Targeting this type of adhesion complex could be a safe and effective therapeutic option to suppress cancer progression.

Authors

Tomofumi Ando, Ikue Tai-Nagara, Yuki Sugiura, Dai Kusumoto, Koji Okabayashi, Yasuaki Kido, Kohji Sato, Hideyuki Saya, Sutip Navankasattusas, Dean Y. Li, Makoto Suematsu, Yuko Kitagawa, Elena Seiradake, Satoru Yamagishi, Yoshiaki Kubota

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Figure 4

Deletion of endothelial Flrt2 induces oxygen-glucose uncoupling in tumors.

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Deletion of endothelial Flrt2 induces oxygen-glucose uncoupling in tumor...
(A) Volcano plot showing the amount of metabolites in Flrt2iΔEC mice relative to that in control mice. The red dots represent 13C-labeled metabolites of the pentose phosphate pathway (PPP), which were significantly reduced in Flrt2iΔEC mice. The horizontal dotted line represents a P value of 0.05. Mice were pretreated with 13C6-glucose to reveal differences in glucose metabolism pathways within the tumor. (B–D) Relative intracellular levels of components of PPP, the glycolytic system, and the TCA cycle, as measured by IC-MS analysis (peak area/internal standard/tissue mg) (n = 3 [control], 4 [Flrt2iΔEC]). (E–L) Representative images showing intratumoral distribution of glucose metabolites, as assessed by imaging mass spectrometry (IMS). Representative images for 3 independent experiments are shown. (M) Amount of 2-deoxy-D-glucose (2-DG) leaking from blood vessels and accumulating in tumor cells, as quantified by IC-MS analysis (n = 3 [control with 2-DG], 3 [control without 2-DG], 3 [Flrt2iΔEC]). 2-DG is converted to 2DG-6P intracellularly and then accumulates in the tumor (see Supplemental Figure 7). (N–Q) IMS showing the amount and localization of 2DG-6P and 2,3-DPG. Arrowheads indicate colocalization of 2DG-6P and 2,3-DPG in the hemorrhagic area. Representative images for 3 independent experiments are shown. Scale bars: 2 mm (E–L and N–Q). Data are presented as the mean ± SD. Comparisons between mean values of 2 groups were evaluated using a 2-tailed Student’s t test. IMP, inosine monophosphate.