Theme 6 : Role of endothelial cell plasticity and metabolic reprogramming in diseases, Atip-Avenir
Presentation of the research topic
The endothelium plays an indispensable role in all tissues, and its dysfunction contributes to a variety of cardiovascular disorders, including atherosclerosis, as well as cancer. Therefore, targeting dysfunctional blood vessels represents a promising avenue for the development of therapies aimed at preventing or treating the most prevalent diseases.Our research aims at characterizing the role of endothelial cell (EC) dysfunction in the onset and progression of cardiovascular diseases and cancer. Specifically, we focus on EC plasticity and associated metabolic reprogramming as drivers of disease progression.By combining multidisciplinary expertise and using advanced molecular and cellular approaches, as well as in vivo mouse models, our team strives to decipher the complex mechanisms regulating the pathological transdifferentation of ECs into mesenchymal-like cells (endothelial-to-mesenchymal transition, EndMT) with the ultimate goal to identify novel means to target this process. Our work is part of a translational approach aiming, in the long-term, at translating our discoveries into clinical applications to improve the care of patients suffering from cardiovascular diseases and cancer.
Key-words
Vascular biology; endothelial cells; endothelial plasticity; vessel permeability; metabolism; metabolic heterogeneity.
Anna Rita Cantelmo
Team leader
anna-rita.cantelmo[@]univ-lille.fr
I began my scientific journey by pursuing a PhD in Dr. Adriana Albini's lab at MultiMedica, Milan (Italy), where I focused on developing innovative strategies to target tumor angiogenesis. After my PhD, I joined the lab of Prof. Peter Carmeliet at VIB-KUL, Leuven (Belgium), where I explored the role of the glycolytic regulator PFKFB3 in endothelial cell metabolism and its impact on angiogenesis and cancer progression. This research resulted in significant publications that enhanced my expertise in vascular biology. In 2018, I relocated to France, where I obtained funding to pursue independent research on angiogenesis at the University of Lille. Recently, I was awarded the Atip-Avenir grant, and I am now performing my research at U1011 at the Institut Pasteur de Lille, focusing on how endothelial cell abnormalities contribute to cardiovascular diseases.
Cyril Robil
Engineer
cyril.robil[@]pasteur-lille.fr
I am an engineer working at the Institut Pasteur de Lille since 2020. I hold a master degree in biotechnology from the University of Lille and a bachelor degree in biology/biochemistry from the University of Orléans. My previous work focused on research projects related to COVID-19, including the study of cellular senescence and the impact of the gut microbiota in disease development. I managed several projects, supervised interns, and participated in scientific collaborations. Before that, I worked as a laboratory technician at GENFIT, where I contributed to develop treatments for liver diseases, specializing in proteomic and transcriptomic analyses. My skills include expertise in cellular and molecular biology, project management, and proficiency using biotechnological equipment.
Mauro Vedelago
Post-doc
Passionate by cancer biology, I obtained my BSc in Biotechnologies in 2016 and my MSc in Molecular Biotechnology in 2018 while working in the lab of Prof. Paola Defilippi, enrolled in different project with the aim to elucidate the impact of the p140Cap scaffold protein on breast cancer cells and tumor microenvironment. In 2019, I moved to Marseille after having earned a PhD position in the lab of Dr. Christophe Ginestier and Prof. Emmanuelle Charafe-Jauffret. I then obtained my Doctoral degree in November 2023 with a thesis entitled “Origin of Drug-Tolerant Persister cells (DTP) in Triple Negative Breast Cancer (TNBC)". In February 2024, I joined U1011 at the Institut Pasteur de Lille as the leader of a new INCa-funded project titled “IMPROVE - Dissecting Metabolic Heterogeneity in Esophageal Cancer to Increase Immunotherapy Efficacy and Overcome Resistance.” This project aims to elucidate the (spatial) composition of the esophageal adenocarcinoma (EAC) microenvironment to better understand the mechanisms behind chemo-immunotherapy resistance.
Fabiola Silva Angulo
Post-doc
fabiola.silva[@]pasteur-lille.fr
I obtained my major of Doctor in Veterinary Medicine degree in 2014 from the Universidad de Concepcion in Chile. After graduation, I moved to the US to purse a PhD at Colorado State University under the menthorship of Dr. Angelo Izzo and Dr. Marcela Henao Tamayo. There, I analyzed and characterized the immune response following administration of BCG vaccination via different routes, as well as the innate and adaptive immune responses to Mycobacterium tuberculosis. During this period, I was awarded both the APEC and the Infectious Disease and Research Response Network (IDR2N) grants, which allowed me to perform part of my research in the team Bronchial Remodeling at the Universite de Bordeaux under the guidance of Dr. Laurence Delhaes. After completing my PhD in 2021, I started my first postdoctoral fellowship in the team Influenza Immunity and Metabolism (I2M) at the Institute Pasteur de Lille under the advisory of Dr. Francois Trottein. There, I led a project investigating how targeting the circadian clock can improve Pneumococcal Pneumonia outcomes in the mouse model. After finishing that project, I joined the team of Dr. Anna Rita Cantelmo to lead the project ‘Uncovering gene signatures of endothelial-to-mesenchymal transition in pathological angiogenesis’ aiming to characterize the role of endothelial-mesenchymal transition (EndMT) in atherosclerosis.
Louay Bettaieb
PhD student
My research interests focus on exploring the complex mechanisms governing vascular biology, particularly how endothelial cells reprogram their metabolism during disease progression. With a BSc in Cell Biology and Physiology (2020) and an MSc in Health Biology and Precision Health (2022) from the University of Lille, I am now pursuing a PhD investigating the role of a mitochondrial protein import machinery in angiogenesis and how its alterations contribute to both cancer and cardiovascular diseases. Alongside my academic work, I have gained valuable experience working with clinical, research, and private sector teams, which has broadened my perspective and strengthened my ability to translate scientific findings into practical applications. By combining advanced molecular techniques and in vivo models, I aim to contribute to the development of innovative therapies that target vascular dysfunction and improve patient outcomes.
Amani Machmouchi
PhD student
amani.machmouchi[@]univ-lille.fr
Passionate about biology and medical research, I obtained my Bachelor degree in Biology at the Lebanese University, followed by an M1 in Animal Biology and an M2 in Research in Immunology. In addition, I also pursued an M1 in Health Administration. Currently, I am a PhD student at U1011 at the Institut Pasteur de Lille, working on the project "Endothelial-to-Mesenchymal Transition (EndMT) in pathological angiogenesis," with a focus on atherosclerosis. My research aims to uncover the mechanisms involved in EndMT and its role in vascular diseases.
Evan Courmont
PhD student (in co-supervision with Prof. Dimitra Gkika, CANTHER)
evan.courmont.etu[@]univ-lille.fr
Fascinated by science, I completed a BSc in Cellular Biology and Physiology in 2021 and obtained my MSc in Biology and Health (Oncology section) in 2023. Since my master’s, I have been working in the team of Dr. Anna Rita Cantelmo, where I initially explored the role of nuclear receptors in endothelial cell functions. Currently, I am pursuing my PhD in co-supervision with Prof. Dimitra Gkika (Canther Lab, UMR9020 CNRS - UMR-1277 Inserm), investigating the impact of calcium signaling, particularly mitochondrial calcium, in EndMT (endothelial-to-mesenchymal transition) and associated diseases, including lung fibrosis.
Recent publication:
“Integrated single-cell RNA-seq analysis reveals mitochondrial calcium signaling as a modulator of endothelial-to-mesenchymal transition”, Lebas M. et al., Science Advances, 2024.
Endothelial-to-mesenchymal transition (EndMT), essential in embryonic development and linked to cardiovascular diseases, remains complex to modulate. Using single-cell RNA sequencing, we identified EndMT conserved gene signatures and found that mitochondrial calcium uptake is a key driver of EndMT. Inhibiting the mitochondrial calcium uniporter (MCU) prevented EndMT in vitro, and MCU deletion blocked mesenchymal activation in a disease model. Elevated MCU levels were also found in patients with critical limb ischemia. These findings suggest MCU as a potential therapeutic target for treating EndMT-related diseases.
Team news (October 2024):
Our postdoc Mauro, along with other members of the unit, recently participated in the "Journée Européenne du Patrimoine 2024." They explained to various non-scientist groups the role of a researcher and the main research focuses of U1011.
Our PhD student Louay Bettaieb will be soon spending three months in Leuven, Belgium, during his PhD mobility period. He will be joining the lab of Prof .Peter Carmeliet at VIB-KUL to gain new (vascular) expertise and generate final data for the completion of his PhD thesis.
Press-releases :
https://www.inserm.fr/en/news/anna-rita-cantelmo-when-the-blood-vessel-cells-malfunction/
https://www.instagram.com/insermnordouest/p/DBY_TmuoXYu/?img_index=1
Our team has expertise in vascular biology, focusing on the characterization of endothelial cell functions in both healthy and diseased conditions such as atherosclerosis, fibrosis, and cancer. We have established a protocol for isolating primary endothelial cells from umbilical cords collected from donors at the CHU hospital. This enables us to create primary in vitro cultures of endothelial cells, which we can use in various functional approaches to assess permeability, calcium homeostasis, and metabolic pathways, specifically in relation to EndMT. We have developed multiple transgenic mouse lines to study endothelial cell dynamic and plasticity in both healthy and pathological states. Furthermore, the team is currently developing expertise in spatial transcriptomics, having received training in the cutting-edge Visium HD pipeline from 10X Genomics.
Lebas M*, Chinigò G*, Courmont E*, Bettaieb L*, Machmouchi A, Goveia J, Beatovic A, Van Kerckhove J, Robil C, Angulo FS, Vedelago M, Errerd A, Treps L, Gao V, Delgado De la Herrán HC, Mayeuf-Louchart A, L’homme L, Chamlali M, Dejos C, Gouyer V, Garikipati VNS, Tomar D, Yin H, Fukui H, Vinckier S, Stolte A, Conradi LC, Infanti F, Lemonnier L, Zeisberg E, Luo Y, Lin L, Desseyn JL, Pickering J, Kishore R, Madesh M, Dombrowicz D, Perocchi F, Staels B, Pla AF, Gkika D, Cantelmo AR.
Integrated single-cell RNA-seq analysis reveals mitochondrial calcium signaling as a modulator of endothelial-to-mesenchymal transition
Sci Adv. 2024 Aug 9;10(32)
Dejos C, Gkika D, Cantelmo AR.
The Two-Way Relationship Between Calcium and Metabolism in Cancer.
Front. Cell Dev. Biol., 2020 Nov 13;8:573747.
Veys K, Fan Z, Ghobrial M, Bouché A, García-Caballero M, Vriens K, Conchinha NV, Seuwen A, Schlegel F, Gorski T, Crabbé M, Gilardoni P, Ardicoglu R, Schaffenrath J, Casteels C, De Smet G, Smolders I, Van Laere K, Abel ED, Fendt SM, Schroeter A, Kalucka J, Cantelmo AR, Wälchli T, Keller A, Carmeliet P, De Bock K.
Role of the GLUT1 Glucose Transporter in Postnatal CNS Angiogenesis and Blood-Brain Barrier Integrity.
Circ Res. 2020 Jul 31;127(4):466-482.
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.
Conradi LC*, Brajic A*, Cantelmo AR*, Bouché A, Kalucka J, Pircher A, Brüning U, Teuwen LA, Vinckier S, Ghesquière B, Dewerchin M, Carmeliet P. Tumor vessel disintegration by maximum tolerable PFKFB3 blockade.
Angiogenesis. 2017 Nov;20(4):599-613.
Cantelmo AR*, Conradi LC*, Brajic A*, Goveia J*, Kalucka J, Pircher A, Chaturvedi P, Hol J, Thienpont B, Teuwen LA, Schoors S, Boeckx B, Vriens J, Kuchnio A, Veys K, Cruys B, Finotto L, Treps L, Stav-Noraas TE, Bifari F, Stapor P, Decimo I, Kampen Kim, De Bock K, Haraldsen G, Schoonjans L, Rabelink T, Eelen G, Ghesquière, B, Rehman J, Lambrechts D, Malik AB, Dewerchin M, & Carmeliet P.
Inhibition of the glycolytic activator PFKFB3 in endothelial cells induces tumor vessel normalization, impairs metastasis and improves chemotherapy
Cancer Cell. 2016 Dec 12;30(6):968-985.
Anna Rita CANTELMO
Institut Pasteur de Lille, U1011-EGID
1 rue du Professeur Calmette
59000 LILLE - France
e-mail: anna-rita.cantelmouniv-lille.fr
office: +33 320 87 71 48