Since 2001’s discovery of microRNAs (miRNAs) in humans, progress in genomics and transcriptomics has increased our comprehension of gene expression regulation. miRNAs are small, noncoding RNA molecules showing huge promise as clinical biomarkers and diagnostic tools for illness and disease, as significant changes in their expression occur in response to pathological states. However, miRNA detection is still challenging nowadays, since costly, complex sample preparations and RNA amplifications are not yet reliable enough for clinical decision making. In this context, three innovative EU companies, Optoi Microelectronics - with microelectronic knowhow and manufacturing skills - DestiNA Genomics - with ‘error free’ chemical technology for microRNAs recognition – and GeneXplain – with bioinformatic capabilities - joined forces with four key academic research groups from the Universities of Trento (Italy), Granada (Spain), Hannover Medical School (Germany) and Santa Catarina (Brazil). All the parties combined their knowledge with respect to miRNA biomarkers with a particular focus on lung cancer, to develop a novel and reliable miRNA detection system for this disease. To this end, research collaborations will address the analysis of miRNAs specifically over-expressed in lung cancer, continuing experimental work already started in the past years, but with greater integration and focus. Existing close partnerships with healthcare institutions will be strengthened, ensuring multi-site and multi-ethnic sampling. In parallel, optimization and validation of a miRNA detection kit based on Optoi semiconductor optical detector will continue. The DestiNA patented technology for specific nucleic acid recognition will be refined to reach the integration and result reliability required for use in clinical point of care testing. The strong network created between the companies and the academic institutions will thus provide a unique scientific and technological environment to turn the research outputs into an innovative product for healthcare advance and progress.

Paediatric high-grade gliomas (pHGGs) are malignant, deadly tumours developing in infants and children. Mutations in histone coding genes disturb epigenetic regulation and in cooperation with other oncogenes promote tumour initiation and progression. pHGGs are fast-growing and diffusive which makes them hard to remove or treat. Surgery (unattainable in midline brain regions) and radiotherapy (RT) remain the only option with transient benefits as median survival is 9-15 months. Those tumours are immunosuppressed, thus immunotherapy is ineffective. We propose that knowledge of tumour-host interactions in the tumour microenvironment (TME) would reveal novel targets allowing to find new ways to eradicate mutated tumour cells, improve efficacy of RT, and reinvigorate anti-tumour immunity. To achieve these ambitious goals we built up the international, multidisciplinary consortium HIT-GLIO. We will i) use latest single-cell technologies and multimodal imaging to characterise tumour-immune cell interactions in a large spectrum of pHGG patient samples; ii) create cellular and animal models of increasing complexity: human glioma-microglia co-cultures, DIPG-derived organoids complemented with iPSC-derived immune cells and syngeneic pHGG mouse models which would be platforms for mechanistic studies and drug screening; iii) evaluate hypoxia-inducible epigenetic inhibitors and blockers of tumour-host interactions to improve RT and immunotherapy responses; iv) generate nanocarriers functionalised to target immune cells and deliver drugs to the brain; v) develop more effective CAR-T cells that together with TME reprogramming and RT would boost anti-tumour immunity; vi) assess neurodevelopmental alterations and psychological consequences of disease and foster psychological approaches to increase quality-of-life of patients and caregivers. The expected outcomes of HIT-GLIO would ultimately pave ways to new clinical trials to improve the way pHGGs are treated. This action is part of the Cancer Mission cluster of projects on “Understanding (tumour-host interactions).

Chromatinopathies (CPs) are a group of rare genetic diseases, which share clinical features as well as causal genetic alterations, leading to the inactivation of chromatin regulators involved in gene expression control and 3D chromatin organization. Within the framework of Chrom_Rare, we will focus on a group of clinically well-defined CPs, including Kabuki Syndrome, Charge Syndrome, Rubinstein-Taybi Syndrome and Cornelia de Lange Syndrome. Although the causative genes for these CPs have been identified, the consequences of their inactivation both at the molecular and functional level, have not been defined. The clinical features of CPs vary widely, suggesting that the impact of the haploinsufficiency of the affected chromatin regulators could depend on the epigenetic state and/or interactions with additional genetic and environmental factors. Hence understanding the genetic and epigenetic determinants of CPs represent an immediate medical need, as this will ultimately facilitate reaching the development of new therapeutic approaches. Our main goal is to set-up an intra-sectoral, cross-disciplinary training programme that would prepare the next generation of researchers equipped with advanced theoretical, technical and computational skills to study fundamental aspects of chromatin biology and their impact on CPs. In parallel, Chrom_Rare will devise new strategies to translate the molecular findings into new diagnostic and therapeutic approaches for patients affected by CPs. To enable understanding the molecular basis of chromatinopathies, we aim at developing multiple disease models recapitulating the main clinical features of CPs (WP1), investigating the genetic, epigenetic and topological determinants of CPs (WP2) and uncovering perturbed regulatory circuitries suitable for therapeutic intervention (WP3). Overall Chrom_rare will address unmet socio-economic, medical and scientific needs, for the understanding and possible treatment for CPs.