Descrizione del progetto
Ingegneria del genoma per modellare l’insorgenza dei tumori
Indipendentemente dalla cellula di origine, i tumori seguono gli stessi principi per quanto riguarda il loro sviluppo accumulando modifiche genetiche tra cui mutazioni, amplificazioni o delezioni di parti del DNA, note come alterazioni del numero di copie. Il progetto MACHETE, finanziato dal Consiglio europeo della ricerca, si propone di studiare l’impatto funzionale delle alterazioni del numero di copie. I ricercatori utilizzeranno un nuovo strumento di ingegneria genomica per introdurre tali alterazioni nel genoma delle cellule pancreatiche e modellare lo sviluppo del cancro pancreatico. Inoltre, il lavoro svelerà informazioni importanti sul ruolo delle aberrazioni genetiche nelle metastasi e nella risposta alla terapia e potrebbe svelare nuovi bersagli di valore terapeutico.
Obiettivo
Cancers arise through genetic and epigenetic alterations that drive the transformation of single cells into malignant tumors. Among genetic changes, copy number alterations (CNAs) are recurrent chromosomal events that increase or decrease the dosage of specific regions of DNA, can affect up to 30% of a cancer cell genome, and are associated with poor clinical outcomes. Despite their pervasiveness, the functional effects of specific CNAs on cancer phenotypes remain largely unknown, as current approaches cannot faithfully recapitulate the unique properties of these chromosomal alterations. Indeed, CNAs can uniquely affect the expression of hundreds of linked genes and change DNA topology, which in turn can promote intra-tumor heterogeneity as illustrated by random segregation of oncogenes in extra chromosomal DNA (ecDNA). In order to study the functional role of CNAs in cancer, this proposal employs MACHETE, a novel genome engineering toolkit that enables the generation of megabase-sized deletions, gains, and oncogene amplification in ecDNA. Using pancreatic ductal adenocarcinoma (PDAC) as a disease model, we will engineer the major CNAs in this lethal tumor to dissect their role in immune evasion, metastasis, and response to therapy. Additionally, through sequential engineering we will study whether the order of CNA acquisition leads to divergent or convergent phenotypes, a highly relevant yet unexplored aspect of cancer biology. Overall, by combining the MACHETE genome engineering platform with in vivo cancer models and molecular approaches, this proposal will begin to systematically dissect the function of recurrent CNAs in PDAC, with direct implications for therapy. Importantly, the methods and conceptual framework of this proposal are broadly applicable to other cancers and diseases characterized by similar chromosomal alterations, where understanding their underlying biology may lead to a new class of CNA-based clinical targets.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
ERC - Support for frontier research (ERC)Istituzione ospitante
08035 Barcelona
Spagna