Role of Endothelial Cells (EC) plasticity and metabolic reprogramming in diseases (Atip-Avenir) 

INSERM U1011 – Université de Lille – CHU Lille – Institut Pasteur de Lille

Team presentation

EndMT process: Following environmental stimuli, ECs progressively loose their identity by downregulating the canonical endothelial markers (CD31, VE-cadherin, vWF) and acquiring the expression of mesenchymal markers (a-SMA, fibronectin, N-cadherin) and transcription factors (SNAI1, SLUG, ZEB2, TWIST) leading to dysfunctional vessels.

Projects

 PROJECT 1 (Louay BETTAIEB; Alina ERRERD) – Fundings : Université de Lille ; Erasmus+ / Inserm

A novel anti-angiogenic strategy targeting dysfunctional AIF/CHCHD4 pathway

(Collaboration : Dr Fabrice SONCIN, LiMMS/IIS, Lille ; Dr Nazanine MODJTAHEDI, UMR CNRS 5261 – INSERM U1315 – Université Claude Bernard Lyon)

Mitochondria are the powerhouse of the cells and to function correctly they must import their proteome via an import machinery pathway, the core component of which is the oxidoreductase CHCHD4. This latter catalyzes the oxidative folding of proteins implicated in many cellular functions including the regulation of mitochondrial metabolism, therefore any alteration of this pathway is associated with cellular dysfunction and ultimately disease.

This project focuses on the characterization of CHCHD4 pathway in endothelial cells. CHCHD4 targeting negatively impacts key cellular functions, as well as mitochondrial metabolism, leading to blood vessels abnormalities. The results obtained until now depict CHCHD4 as an important regulator of EC physiology and homeostasis. Assessing the role of this pathway in ECs will contribute to identify novel mechanisms which are altered and can be target in dysfunctional blood vessels.

PROJECT 2 (Amani MACHMOUCHI ; Fabiola SILVA ANGULO) – Fundings : Université de Lille 

Uncovering gene signatures of endothelial-to-mesenchymal transition in pathological angiogenesis

(Collaboration: Pr Dimitra GKIKA, CANTHER, Lille)

This project aims to characterize the role of endothelial-mesenchymal transition (EndMT) in pathologies such as cancer and atherosclerosis. In previous studies we identified calcium signaling as a driver of physiological EndMT, with this project we extend our investigations to pathological EndMT in order to identify EndMT gene signatures associated with disease. We use advanced omics approaches combined with in vitro and in vivo models to assess the possibility of targeting calcium signaling to inhibit EndMT. This research may open new therapeutic avenues for pathologies associated with EndMT.

PROJECT 3 (Evan COURMONT) – Fundings : Région HdF-Pasteur

The role of nuclear receptors in endothelial cell function

(Collaboration: Pr Dimitra GKIKA, CANTHER, Lille)

Nuclear receptors (NR) are a family of ligand-regulated transcription factors activated by lipid-soluble signals. Once activated, NR control the transcription of genes involved in a variety of biological processes, including proliferation, differentiation and metabolism.

The vasculature is the interface between blood circulation and underlying tissue, and as such is exposed to several NR activators. Despite evidences highlighting the role of NR in vascular biology, we still have limited knowledge on the action mechanisms in cells of vascular origin.

The aim of this project is to developed a NR atlas of human endothelial cells to identify potential candidate receptors that may play a role in vascular stability.

PROJECT 4 (Mauro VEDELAGO; Cyril ROBIL) – Fundings : INCa-DGOS

Dissecting metabolic heterogeneity to increase immunotherapy

(Collaboration: Pr Guillaume PIESSEN, CHU Lille)

Metabolic heterogeneity is a crucial determinant of tissue function and, in many diseases, it is responsible of therapy failure. This is the case of tumors, where different cells in the microenvironment engage in metabolic crosstalk with other stromal cells (for example, between endothelial cells and fibroblasts) and/or immune cells to acquire a dysfunctional phenotype contributing to disease progression and anti-cancer therapy resistance. We aim to dissect the metabolic heterogeneity within highly aggressive and resistant esophageal cancer. Through a translational approach using human tissues and cutting-edge technologies, including omics, we will assess how metabolic heterogeneity among different cell populations contributes to mechanisms associated with resistance to immune checkpoint inhibitors. The ultimate goal is to identify novel metabolic targets in endothelial cells that can be exploited to improve the overall survival of esophageal cancer patients and overcome current therapeutic limitations.

Transversal Projects

Target endothelial plasticity to inhibit acute leukemia progression and resistance

(Collaboration : Dr Diana PASSARO, Institut Cochin, Paris; Dr Leïla PERIE’, Curie Institute, Paris – Financeur : La Ligue Contre Le Cancer)

Effects of ionophorous antibiotics on endothelial cell functions 

(Collaboration : Pr Luigi LANZA, University of Padua, Italy)

Fundings

Members

Alumnis

Key Publications

Eelen G*, Dubois C*, Cantelmo AR, Goveia J, Brüning U, DeRan M, Jarugumilli G, van Rijssel J, Saladino G, Comitani F, Zecchin A, Rocha S, Chen R, Huang H, Vandekeere S, Kalucka J, Lange C, Morales-Rodriguez F, Cruys B, Treps L, Ramer L, Vinckier S, Brepoels K, Wyns S, Souffreau J, Schoonjans L, Lamers WH, Wu Y, Haustraete J, Hofkens J, Liekens S, Cubbon R, Ghesquière B, Dewerchin M, Gervasio FL, Li X, van Buul JD, Wu X, Carmeliet P. *equal contribution
Role of glutamine synthetase in angiogenesis beyond glutamine synthesis.
Nature. 2018 Sep;561(7721):63-69.

Keywords

Contact of the team

Anna Rita CANTELMO
Team Leader

ORCID :
0000-0002-2748-264X

anna-rita.cantelmo@univ-lille.fr
+33 3 20 87 71 48