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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171278 | GEO | 2022/12/31

REPOSITORIES: GEO

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Project description:Invasion of lymphatic vessels is a key step in the metastasis of primary tumour cells to draining lymph nodes. Recent evidence indicates that such metastasis can be facilitated by tumour lymphangiogenesis, although it remains unclear whether this is a consequence of increased lymphatic vessel numbers or alteration in the properties of the vessels themselves. Here we have addressed this important question by comparing the RNA profile of normal dermal lymphatic endothelial cells (LEC) with those isolated from tumours of murine T-241/VEGF-C metastatic fibrosarcoma. Our findings reveal significant changes in the expression of some 792 genes in tumour lymphatics (â?¥ 2 fold up/downregulation, p â?¤ 0.05), involving particularly transcripts associated with junctional adhesion, immunomodulation, extracellular matrix and vessel growth/patterning, several of which we have confirmed by RT-PCR and/or immunohistochemistry. Interestingly, this altered phenotype could not be attributed solely to VEGF-C induced lymphoproliferation, as no similar change in gene expression was reported when human LEC were cultured with VEGF-C in vitro. Moreover, we show that a key protein upregulated in the mouse model, namely the tight junction protein Endothelial Cell Specific Adhesion Molecule (ESAM), is similarly upregulated in tumour lymphatic vessels from 2/2 patients with head and neck squamous cell carcinoma and 4/4 patients with aggressive bladder carcinoma. These findings demonstrate a previously unrecognized influence of tumour environment on lymphatic gene expression and identify candidate tumour specific vessel markers that may prove valuable for either prognosis or therapy. Experiment Overall Design: Here we have investigated the invasion of lymphatic vessels as a key step in the metastasis of primary tumour cells to draining lymph nodes by comparing the gene expression profile of normal dermal lymphatic endothelial cells (LEC) with those isolated from tumours of murine T241/VEGF-C/GFP metastatic fibrosarcoma. Three biological replicates were analyzed from each group.

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

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