The aim of the MOlecular-Scale Biophysics Research Infrastructure (MOSBRI) is to enable ambitious integrative multi-technological studies of biological systems at the crucial intermediate level between atomic-resolution structural descriptions and cellular-scale observations. Its consortium of 2 companies and 13 academic centres of excellence from 11 countries gathers a wide complementary panel of cutting-edge instrumentation and expertise, leveraging barriers that currently hinder the optimal exploitation of molecular-scale biophysical approaches in the fields of biomedicine, biotechnology, biomaterials and beyond. MOSBRI provides European academic and industrial researchers with a one-stop shop Trans-National Access to the latest technological developments in advanced spectroscopies, hydrodynamics, thermodynamics, real-time kinetics and single molecule approaches. It will play a major role in standardization and policy-making in the field by: i) carrying out Joint Research Activities to develop innovative methodologies; ii) designing robust quality control guidelines and FAIR-compatible archiving formats and databases; iii) engaging with instrumentation, pharma, biotech and CRO SMEs. Networking activities will multiply the impact of MOSBRI, by efficiently sharing and disseminating theoretical and practical knowledge through training events in Europe, contributing to: i) the emergence of a highly qualified new generation of scientists; ii) outreach to scientific communities currently unaware of the full potential of the integrated use of molecular-scale biophysics tools. MOSBRI is complementary to related infrastructures including INSTRUCT-ERIC and iNEXT-Discovery, and will help creating a strong cross-fertilizing ecosystem with leveraging effects for European science. It represents a unique opportunity for Europe to remain at the forefront in this competitive field, thereby contributing significantly to the acceleration of discoveries beneficial for OneHealth.

It sounds simple: A cell cannot divide without nucleotides. Indeed, the disruption of pyrimidine de novo synthesis (PDNS) efficiently blocks proliferation of cancer cells. Yet still today, PDNS-directed anticancer treatment has not entered clinics due to the lack of efficacy. Why? Cancer cells gain pyrimidines via PDNS or from salvage pathways, and PDNS inhibition in cancer cells can likely be bypassed by pyrimidines produced in the tumor environment or gained from the systemic circulation. Can we target this microenvironmental interaction to improve treatment efficacy? A crucial component of tumor environment are blood vessels. Tumors stimulate their growth, angiogenesis, to gain oxygen and nutrients. Metabolism of endothelial cells (ECs), the inner vessel lining, is rewired in tumors, and tumor ECs upregulate PDNS. However, whether and how elevated PDNS in ECs supports tumorigenesis is unknown. I hypothesize that PDNS in ECs affects tumor environment either directly by providing pyrimidines to cancer cells or indirectly by stimulating angiogenesis, making systemic resources more accessible to cancer cells. The central goals of this project are (i) to identify the metabolic communication of ECs with other cell types in tumors, (ii) asses if endothelial PDNS promotes angiogenesis, and (iii) to seek novel metabolic targets in ECs, whose inhibition improves efficacy of PDNS inhibitors in vivo. To reach these goals, I will use an inducible mouse model to selectively disable PDNS in the endothelium. With this unique tool available at my host institute, I will integrate a state-of-the-art multi-omics and my expertise in metabolism to disentangle the network of metabolic communication using a powerful combination of spatially resolved single cell transcriptomics, metabolomics and functional genomics. My innovative approach will open a way for understanding the EC contribution to metabolic balance in tumors with a potential to identify new metabolic anti-cancer strategies.

Microtubules (MT) are core components of the eukaryotic cytoskeleton with essential roles in cell division, cell shape, intracellular transport, and motility. Despite their functional divergence, MTs have highly conserved structures made from almost identical molecular building blocks – tubulin proteins. A variety of posttranslational modifications (PTMs) diversifies these building blocks, which is thought to control most of the properties and functions of the MT cytoskeleton, a concept referred to as the ‘tubulin code’. While they appear to have subtle effects at the molecular level, tubulin PTMs are essential for maintaining cellular functions of MTs over large spatial and temporal scales. Yet, a comprehensive knowledge of the principles of the tubulin code, connecting its functions across the molecular, cellular and organismal levels, is almost entirely lacking. Our project aims to obtain a novel molecular and mechanistic understanding of how tubulin PTMs control long-term cellular function and homeostasis. Our unique approach bridges all relevant scales of biology and relies on a synergy between our powerful experimental models and expertise in biochemistry, structural biology, single-molecule assays, systems-biophysics, cell biology, and physiology. Specifically, we will: (1) Determine how different tubulin PTMs affect biophysical and structural properties of MTs and their interactions with associated proteins; (2) Define the impact of tubulin PTMs on overall MT cytoskeleton behaviour and the resulting physiological implications in neurons; (3) Combine zebrafish and mouse models and develop a novel fish model for lifelong in-vivo imaging to determine how the tubulin PTMs control lifelong MT-based functions. Our work will define the importance of tubulin PTMs by revealing their critical molecular functions over the lifetime of an organism. The project has the potential to substantially change our perception of the cytoskeleton’s role in homeostasis and disease.