DECODING AND TARGETING TRANSLATION IN HEALTH AND DISEASED ANGIOGENESIS
Translation is the biological process where the genetic codons are decoded from mRNA to protein by ribosome translocation. Translation is a highly and tightly controlled mechanism for cell identity and function. Approaches investigating translation regulation in EC remain neglected. 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. Our final goal 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.
ENDOTHELIAL METABOLIC CONTROL
DURING ATHEROSCLEROSIS
Atherosclerosis is an inflammatory disease resulting in the hardening and thickening of the wall of arteries and forming plaques, which comprise immune cells, mesenchymal cells, lipids, and extracellular matrix. During atherosclerosis, there is a buildup of fats, cholesterol, and other substances in the artery walls. This buildup is called plaque. The plaque can cause arteries to narrow, blocking blood flow and leading to a blood clot. Atherosclerosis can be treated. Endothelium lining the aorta wall is the source of plaque-associated mesenchymal cells. Endothelial cells can acquire a mesenchymal phenotype through endothelial-mesenchymal transition (EndMT). Blocking such EndMT can prevent or ameliorate atherosclerosis. We are investigating the role of endothelial metabolic pathways that can help prevent atherosclerosis or even cure it. Our results demonstrate that endothelial metabolism is required to maintain endothelial vs mesenchymal cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.
DECODING MELANOMA INVASIVENESS AND SPREADING BY SPATIAL TRANSCRIPTOMICS
Cancer formation and spreading are influenced by how gene expression is spatially distributed, within tissue and organ. Understanding of these phenomena has substantially improved in the past decade with the emergence of spatial transcriptomics - a variety of methods for comprehensively quantifying and mapping transcriptional activity. Spatial transcriptomics allows the generation of topographical images of gene expression across a tissue sample, identifying individual cells, defining clusters of cellular phenotypes, and how these interact with each other and their surrounding environment. We exploited GeoMx Digital Spatial Profiler (DSP) to define microscopic regions of interest on an human primary melanoma tissue. We discovered specific molecular features within the tumor microenvironemnt (TME) that are used by melanoma tumor cells to invade and spread into lymphatic vs endothelial vessels. We are planning to decode such molecular and metabolic pathways to develop new therapeutic strategies on primary and relapse melanoma states.
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 and the goal of this project is to unravel such mechanisms 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
THE ROLE OF MECHANOBIOLOGY AND
LIPID METABOLISM IN METASTASIS
Altered lipid metabolism is among the most prominent metabolic alterations in cancer progression. The role of isoprenoid lipid metabolism and signaling is left behind in metastasis formation and spreading. Our recent findings indicate that circulating tumor cells (CTCs) alter mechano-signaling to influence isoprenoid pathway and metabolite to survive. Here we address the role of mechanobiology and isoprenoid metabolism in regulating melanoma progression with a particular focus on sensitize metastatic cells to anticancer therapy.