Type 2 diabetes (T2D) is a major public health problem, affecting 55 million European citizens. T2D ensues in individuals who develop a progressive pancreatic beta cell failure. T2D probably comprises a heterogeneous group of diseases. A new molecular taxonomy of T2D is essential for the development of medical care that is predictive, preventive and personalized. Currently available T2D therapies are not disease modifying: they treat hyperglycaemia without addressing its underlying cause, i.e. beta cell failure. In this proposal we seek to identify pathogenic molecular events that operate in the diseased tissue, i.e. the failing human beta cell, at their true level of complexity. T2DSystems will accomplish this ambitious goal by integrating human islet genetic and epigenetic data with disease-relevant environmental perturbations, metabolomics and functional studies, and use this knowledge to identify distinct human islet phenotypes in subgroups of patients. In closely interacting work packages, we will achieve the following goals: • Compile and expand existing European bio-banks and datasets to create the Translational human pancreatic Islet Genotype tissue-Expression Resource (TIGER), a T2D systems biomedicine resource of unprecedented scale; • Develop large-scale data analysis tools and both data driven and mechanistic probabilistic modelling frameworks to exploit TIGER towards system level biological insight; • Translate these findings to identify stratified beta cell phenotypes in human cohorts. This will provide understanding of beta cell pathophysiology in vivo and enable stratified prevention and therapeutics. T2DSystems will enable the development of personalized diagnostic tests, taking into account individual environmental and genetic risk factors. The newly identified molecular disease mechanisms will provide the basis for development of novel therapies and for patient stratification to test individualized therapies.

Adaptmet aims to develop an advanced training program encompassing the multifaceted aspects of metastasis adaptation mechanisms, intending to equip budding researchers with the necessary skills to emerge as leaders in this field. A robust mentoring and training strategy, coupled with cutting-edge methodologies and a diverse range of complementary soft skills, are crucial to this endeavour. These skills are imparted through local and network-wide events, fostering seamless research progression, and nurturing successful career trajectories. Scientifically, Adaptmet addresses an unmet medical need by harnessing basic science to revolutionize drug development and, ultimately, enhance patient care. Specifically, scientific work packages (WPs) have been designed to approach metastasis from various functional perspectives. In order to metastasize, cancer cells must adeptly coordinate diverse cellular functions (Cell Fate - WP1). Additionally, understanding the intricate interactions between metastatic cells, the host immune system, and tissue stroma is pivotal (Environment – WP2). Crucial aspects such as the kinetics of metastasis and the mechanisms governing latency, particularly, remain inadequately understood (Latency – WP3). Clarifying this complexity, unravelling mechanisms underlying therapy failure, and identifying expansion pathways are central to defining novel therapeutic targets (Expansion – WP4). In essence, Adaptmet stands at the intersection of a rapidly evolving multidisciplinary domain, amalgamating distinct fields that often face challenges in mutual communication. The success of Adaptmet hinges upon robust partnerships, open exchange of ideas, state-of-the-art methodologies and equipment, and the exploitation of synergistic opportunities among network members. This collaboration spans diverse perspectives, bridging gaps between different disciplines, thereby breaking down barriers and fostering interdisciplinary cohesion.

Evomet aims to create a high-level training programme on the various aspects of metastasis evolution in order to provide young researchers with skills to become future leaders in the field. To this end, it is imperative to have a solid mentoring and training strategy, a state-of-the-art scientific approach, and a broad range of complementary soft skills. Collectively, these skills will be provided to each ESR through a series of events (local and network-wide) and initiatives that will allow ESRs to ensure smooth progress of their research projects and a successful career. Scientifically, Evomet has been designed to address an unmet medical need through leverage of basic science to impact drug development and, ultimately, improve how patients are managed. Scientific WPs tackling metastasis from a functional perspective have been defined. To metastasize, cancer cells must orchestrate diverse cellular functions to overcome the challenges inherent in the metastatic cascade (Cell Fate – WP1). These functions are also highly dependent on the interactions of the metastatic cell with the host immune system and tissue stroma (Environment – WP2). However, the kinetics of metastasis and, in particular, the mechanisms that regulate metastasis latency remain poorly understood (Latency – WP3). Mapping this complexity, examining patterns of clonal evolution, mechanisms of therapy failure, and pathways for expansion is central to defining new targets (Expansion – WP4). In summary, we are facing a fast-growing multidisciplinary area created from the aggregation of different fields that have problems communicating with each other. Evomet’s success builds on the strong relations between partners, the open exchange of ideas, state-of-the-art methodology, tools and equipment as well as the exploitation of synergistic opportunities between the network members, covering different perspectives and filling the gap between them, thus breaking the isolation between disciplines.