Lymphatic vessels maintain tissue fluid homeostasis. They also serve as essential conduits for tumor cell dissemination and the removal of cholesterol from the aortic wall. Accordingly, excessive or insufficient lymphangiogenesis (formation of the lymphatic vasculature) underlies the pathogenesis of multiple human diseases such as cancer, lymphedema, and atherosclerosis, for which curative treatments are not available. Thus, a better understanding of the mechanism of lymphangiogenesis may guide the development of new therapeutic strategies.
Our previous study has discovered that a novel cellular mechanism—endothelial glycolysis—plays a crucial role in embryonic lymphangiogenesis . Cells convert glucose into pyruvate through glycolytic metabolism, which generates ATP. Lymphatic endothelial cells (LECs) exhibit robust glycolysis and heavily rely on this metabolic process for ATP production. Accordingly, glycolytic inhibition through genetic ablation of a rate-limiting glycolytic enzyme hexokinase 2 (HK2) profoundly impairs lymphatic vessel development during mouse embryogenesis. Importantly, endothelial glycolysis can be enhanced by fibroblast growth factor (FGF)2 signaling via HK2 and is essential for FGF2-driven lymphangiogenesis. Our study highlights the importance of endothelial glycolysis in early lymphatic vessel formation (Yu et al., Nature, 2017)
More recently, we discovered a molecular mechanism that orchestrates LEC metabolism while sustaining the expression of PROX1, a transcription factor key to lymphatic fate specification and development. In this study, we show that genetic loss of RAPTOR, an indispensable component of mTORC1, in LECs suppresses PROX1 expression, impairs lymphatic capillary growth, and results in defective differentiation of collecting lymphatics. Further analysis reveals that RAPTOR depletion inhibits glycolysis and glutaminolysis in LECs by impacting enzymes involved in the two metabolic pathways, particularly hexokinase 2 (HK2) and glutaminase (GLS). Mechanistically, our data suggest that mTORC1 inhibition downregulates MYC, which in turn suppresses HK2 and GLS expression. Consistent with this finding, ablation of MYC or both HK2 and GLS in LECs impedes lymphatic capillary formation and differentiation of collecting lymphatics. Interestingly, we found that mTORC1 regulation of PROX1 is independent of the MYC–HK2/GLS axis. Moreover, our genetic interaction data indicate that MYC and PROX1 play crucial roles in mTORC1-regulated lymphatic vascular development. Collectively, our findings identify mTORC1 as a key regulator of both metabolic programs and PROX1 expression in LECs. Our work also reveals metabolic processes critical for lymphatic capillary and collecting vessel formation, which may be targeted to repress pathological lymphangiogenesis (Han et al., Developmental Cell, 2025; Zhu et al., Vascular Pharmacology, 2026).
Research projects of our laboratory are built upon these studies to further understand the involvement of cellular metabolism in lymphatic development and disease.