Tumor secretome and VEGF-C induce opposite transcriptomic changes in lymphatic endothelial cells

Within the tumor microenvironment, lymphatic endothelial cells (LEC) contribute to the remodeling and the formation of lymphatic vessels involved in the transport of metastatic and immune cells. Displaying an increasingly recognized plasticity and heterogeneity, tumor-associated LEC are expected to exert additional functions in the primary tumor environment. Using RNA sequencing data, we analyzed the transcriptomic changes induced in LEC in response to two different stimuli from the tumor microenvironment, i.e. vascular endothelial growth factor C (VEGF-C) and the tumor secretome of malignant cells. This analysis revealed that these two stimuli exert contrasting effects leading to distinct transcriptomic switches: a stimulation of pro-inflammatory factors (“secretory transcriptome”) induced by the tumor secretome versus an upregulation of cell cycle-associated pathways (“lymphangiogenic transcriptome”) induced by VEGF-C. These data help to better understand the phenotypic reprogramming of LEC caused by their interaction with tumor cells and pro-lymphangiogenic factors, opening the door for further investigations to decipher the diversity of LEC subpopulations and their diverse roles in lymphangiogenic conditions and the tumor microenvironment. RNA profiling of lymphatic endothelial cells (LEC) stimulated with: (i) conditioned medium of LEC themselves (naive LEC/control; 3 samples), (ii) conditioned medium of HaCaT-II-4 tumor cells (teLEC, 4 samples) , or (iii) VEGF-C at 400 ng/ml (VEGF-LEC, 4 samples)