DECODING AND TARGETING TRANSLATION IN HEALTH AND DISEASED ANGIOGENESIS
Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Translation is the biological process where the genetic codons are decoded from mRNA to protein by ribosome translocation. Once considered as a passive decoding of mRNAs, scientists now perceive it as a powerful modulator of gene expression, thus suggesting that translation is a highly and tightly controlled mechanism for cell identity and function. While transcriptomics studies had offered extensive insight in endothelial cells (EC) biology and demonstrated the importance of transcriptional regulation during angiogenesis (the process of formation of new blood vessels), similar approaches investigating translation in EC remain neglected. Whether EC modulates translation during development or adulthood angiogenesis and whether translation regulation could represent a novel targetable approach for pathological angiogenesis is unclear. Whether and how cell metabolism regulates translation remains elusive. Our goal is to decipher the role of translation in angiogenesis by asking how, when and why such translation mechanisms are engaged by normal and diseased EC. We plan to decode the endothelial translatome landscape and identify single EC translation “hotspots” within subcellular domains. By using genetic, metabolic, and proteomic approaches, we plan to define and characterized novel endothelial metabolic pathways and how they regulate EC-VSMC cross-talk. Our objective is to enable spatial and single-cell translatomic studies and establish translational players as new diagnostic markers to support the clinical potential of translation intervention in anti‐angiogenic therapies. We anticipate our studies to be a starting point for novel anti-angiogenic approaches to overcome anti-VEGF therapies resistance in cancer and other diseases.
ENDOTHELIAL METABOLIC CONTROL DURING ATHEROSCLEROSIS
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the build-up of atheromatous plaque. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. When severe, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney problems, depending on which arteries are affected. The exact cause is not known and is proposed to be multifactorial but involved mainly endothelial cells and vascular smooth muscle cells. Both endothelial cells Vascular mural cells (vMC) play an essential role in the development and maturation of the vasculature by promoting vessel stabilization through their interactions with endothelial cells (EC) in health and in disease. Previous studies have identified a series of endothelial signaling pathways that are critical for mural cell recruitment, differentiation and vascular stabilization. Whether endothelial metabolism also plays an important role in atherosclerosis is less known.
We are investigating the role of endothelial metabolic pathways in vMC coverage of the dorsal aorta (DA) during early vertebrate development. Our results demonstrate that endothelial metabolism is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.
THE ROLE OF LIPID METABOLISM AND SIGNALING IN CANCER PROGRESSION
Lipids are a highly complex group of biomolecules that not only constitute the structural basis of biological membranes but also function as signaling molecules and an energy source. Enhanced synthesis or uptake of lipids contributes to rapid cancer cell growth and tumor formation. Altered lipid metabolism is among the most prominent metabolic alterations in cancer. The role of isoprenoid (mevalonate) lipid metabolism and signaling is left behind. Recent findings indicate that the isoprenoid pathway has several essential outputs in addition to cholesterol, likely important for cancer cell survival. Here we address the role of isoprenoid metabolism in regulating breast cancer and melanoma progression with a particular focus on its regulation of oxidative stress and ferroptosis in circulating tumor cells (CTCs).
NOVEL THERAPEUTIC APPROACHES
IN CORNEAL DYSTROPHIES
Dominant mutations in the human UBIAD1 gene lead to a deregulation of free cholesterol and phospholipid metabolism, producing cornea opacification and visual acuity loss, leading to Schnyder Corneal Dystrophy (SCD). The tissue is damaged by high oxidative stress-mediated by iron which leads to lipid peroxidation. UBIAD1 is an enzyme that catalyzes the biosynthesis of CoQ10 or Vitamin K2 and the goal of this project is to unravel such mechanism to provide therapeutic approaches. The plan of the project is based on giving the possibility to repurpose existing FDA-approved drug deferiprone (an iron chelator) and Coq10 for the SCD treatment model and genetically engineered human limbal stem cells will serve for these studies.