THE SANTORO LAB
University of Padua
DECODING AND TARGETING TRANSLATION IN HEALTH AND DISEASED ANGIOGENESIS
While transcriptomic studies have provided extensive insights into EC biology and demonstrated the importance of transcriptional regulation during angiogenesis, similar approaches investigating mRNA translation in EC have remained overlooked. Translation is the biological process by which genetic codons are decoded from mRNA to protein through ribosome translocation. Once viewed as a passive decoding of mRNAs, scientists now regard it as a powerful modulator of gene expression, suggesting that translation is a highly regulated mechanism critical for cell identity and function. It remains unclear whether EC modulates translation during development or adulthood angiogenesis, and whether translation regulation could represent a novel, targetable approach for pathological angiogenesis. Our goal is to elucidate the role of translation in angiogenesis by exploring how, when, and why such translation mechanisms are engaged by both normal and diseased EC. We will decode the endothelial translatome landscape by identifying translation mechanisms and subcellular “factories” of sprouting EC. We will establish zebrafish and mouse vertebrate models to investigate and visualize the angiotranslatome and its players in health and disease conditions, aiming to foster next-generation translational therapies. Our strategic objective is to enable spatial and single-cell translatomic studies and to establish translational components as new key players in angiogenesis to support the clinical potential of translation interventions in anti-angiogenic therapies.
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.
ROLE OF METABOLISM IN TUMOR IMMUNE RESPONSES
Metabolic rewiring is a defining hallmark of cancer and plays a central role in sustaining tumor growth, progression, and therapeutic adaptation and resistance. Cancer cells continuously remodel their metabolic programs in response to intrinsic genetic alterations and signals from the tumor microenvironment including lymphatic and endothelial cells as well as T cells. Together with transcriptional and translational regulation, these metabolic adaptations shape tumor evolution, metastatic potential, and treatment response. While the impact of cancer metabolism on tumor cell biology is well established, its role in regulating tumor immunogenicity and anti-tumor immunity remains incompletely understood. Our research aims to uncover how metabolic pathways influence the interaction between melanoma cells and the immune system, with a particular focus on melanomas during immunotherapy. Using complementary in vitro, mouse, and patient-derived preclinical models, we are dissecting how specific metabolites generated by the mevalonate pathway regulate anti-PD-L1 response, ultimately shaping the immune response to melanoma. By defining the metabolic mechanisms that drive immune evasion and immunotherapy resistance, our goal is to identify novel therapeutic vulnerabilities and develop innovative combination strategies that improve the efficacy and durability of cancer immunotherapy.