Descrizione del progetto
Uno studio sulle alterazioni cromosomiche potrebbe aiutare la ricerca relativa ai geni del cancro
Oltre un secolo fa, Theodor Boveri fece una serie di importanti scoperte riguardanti le alterazioni cromosomiche che si configurano come forze motrici del cancro. Di recente, i ricercatori hanno iniziato a riconoscere che le alterazioni del numero di copie somatiche (SCNA, somatic copy number alterations) sono una delle più spiccate caratteristiche dei genomi del cancro. Le alterazioni del numero di copie somatiche possono modificare i modelli di espressione di diverse centinaia di geni contemporaneamente. Il progetto CrispSCNAs, finanziato dall’UE, mira ad affrontare le limitazioni negli studi sulle SCNA combinando modellizzazioni avanzate in vivo e in vitro di cancro al fegato con tecnologie di ingegneria genomica innovative definite come brevi ripetizioni palindrome raggruppate e separate a intervalli regolari. Il progetto approfondirà in modo sistematico per la prima volta il ruolo funzionale delle SCNA nella patobiologia del tumore e contribuirà a identificare nuove strategie terapeutiche, specificamente concepite per le singole SCNA.
Obiettivo
In 1914 Theodor Boveri described abnormal chromosome counts in cancer cells and speculated that these alterations are the driving force of cancer. Almost 100 years later it became clear that somatic copy number alterations (SCNAs) are one of the most striking characteristics of cancer genomes. SCNAs comprise deletions and amplifications of whole chromosome arms and therefore alter the expression patterns of several hundred genes simultaneously. These alterations show defined patterns suggesting selective pressure, and thus likely contain multiple driver genes, which can shape several tumorigenic properties. Therefore, studying how these events contribute to tumor development will be fundamental to understand cancer biology and develop targeted cancer therapies. However, whereas the function of recurrently mutated driver genes can be readily assessed, studying SCNAs remains challenging so far. This project will overcome these limitations by combining our unique ability to model liver cancer in vivo and in vitro with innovative CRISPR-based genomic engineering technologies. First, we will generate large chromosomal deletions in murine livers and human-derived liver organoids by CRISPR technologies and assess their functional role in cancer development. Furthermore, synthetic lethal interactions generated by these deletions will be evaluated on their therapeutic potential. Additionally, driver genes and driver gene-combinations of amplified chromosomal regions will be investigated using a novel CRISPR/Cas9-based mouse model for endogenous gene activation and chromosome engineering. Finally, we will exploit a novel concept for targeting cancer cells with specific amplifications. Our unique approach will for the first time systematically investigate the functional role of SCNAs in tumor pathobiology, identify new therapeutic strategies specifically tailored for individual SCNAs, and will therefore have high impact for future efforts to understand and combat cancer.
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Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
69120 Heidelberg
Germania