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-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 anti-tumor effects of immune checkpoint blockers. Mechanistically, we found that FLRT2 forms non-canonical inter-endothelial adhesions that safeguard against oxidative stress through homophilic binding. Together, our results demonstrated the existence of tumor-specific inter-endothelial 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.

Carbon ion irradiation suppresses angiogenic response in human lung adenocarcinoma cells mediated by LINC00167/miR-663a/TGF-β1 axis

“…Given that angiogenesis is essential for tumor metastasis [30,[33][34][35], we wondered whether overexpression or knockdown of LINC00167 would affect the cell metastasis ability of lung cancer cell lines. Furthermore, the migration and invasion ability of cell models was also tested.…”

Single-cell analysis of multiple cancer types reveals differences in endothelial cells between tumors and normal tissues

“…Tumor blood vessels facilitate tumor growth, metastasis, and immune escape [4] , [34] , [35] . Some studies reported increased abundance of tip-like ECs in different single type of tumor tissues, some also explored the molecular characteristics of the tip-like ECs [15] , [36] .…”

Rejection of inappropriate synaptic partners mediated by transcellular FLRT2-UNC5 signaling

“…FLRT and UNC5 proteins are emerging as important contributors to many facets of brain development and disease (Ando et al, 2022; Del Toro et al, 2017; Khani et al, 2022; Klein and Pasterkamp, 2021; Murcia-Belmonte et al, 2019; Yamada et al, 2019). Thus, there has been substantial interest in understanding both the molecular mechanisms by which these proteins function as well as the specific neurodevelopmental events they control.…”