Informace o projektu
Nové molekulární cíle a prognostické markery u neuroblastomu: Identifikace na základě mapování diferenciačních programů buněk neurální lišty

Neuroblastoma (NB) remains a highly lethal pediatric solid tumor accounting for 15% of cancer-related deaths in children. NB shows extensive heterogeneity that dictates its clinical course, ranging from spontaneous regression to treatment-resistant metastatic disease. Several biomarkers, including genetic aberrations, have significantly improved NB risk assessment and treatment assignment. Yet, up to 10% of NB patients diagnosed with low- and intermediate-risk tumors eventually die from progressive disease and survival of high-risk NB patients has plateaued at 60%. NB arises mainly in the adrenal glands and sympathetic ganglia and is thought to originate in the neural crest cell-derived sympathoadrenal lineage. Recent single-cell transcriptomics studies of normal sympathoadrenal development have discovered unprecedented differentiation trajectories and cell state clusters relevant to NB heterogeneity. We have shown in NB cell lines that key cluster-specific genes might be highly informative of the different NB origins and aggressiveness. Expanding on these results and our preliminary data, we propose an internationally collaborative project that will comprehensively investigate selected genes defining the distinct cell phenotypes in the normal sympathoadrenal development to evaluate their potential utility as new therapeutic targets and/or markers refining prognosis in NB. We will utilize NB transcriptomics, tissue sections and patient-derived cell lines to reveal potential correlations between the cell cluster-specific gene expression and clinicopathological features. Promising candidates will be functionally and pharmacologically characterized in NB cells and validated in single-cell transcriptomics datasets and a unique, large cohort of NB tissue samples. This project aims to pinpoint clinically relevant genes/proteins that might reflect developmental origins of NB and that could help to improve risk classification systems or predict novel therapies for NB.