Chromosomal translocations in primary human cells as drivers of oncogenesis
Chromosomal translocations are characteristic of a wide range of cancers and are generally associated with the formation of a new fusion oncogene. These are genomic events resulting from the exchange of pieces of two heterologous chromosomes, which can occur after concomitant DNA breaks. For a long time, the main challenge has been to achieve functional modeling of cancer translocations from primary cells. The use of genome-editing systems has made it possible to overcome this limitation, and it is now possible to model different cancer-specific translocations in the relevant human primary cells, thus reproducing the stochastic nature of single-cell tumor formation in humans. The formation of a chromosomal translocation undoubtedly leads to major alterations in genome organization (including expression, epigenetics and replicative changes). The aim of our studies is therefore to understand the molecular processes leading to these global structural changes, and to identify new drivers of tumorigenesis. This includes the molecular mechanisms leading to chromosomal instability and the identification of genome-wide expression, epigenetics and replication. At the same time, our studies are also designed to understand the underlying biology of tumorigenesis: deciphering the process of cellular transformation from primary human cells to tumors in vivo, including the early stages of pre-transformation. Finally, some tumor types are associated with additional genetic events (somatic mutations but also other catastrophic genomic events such as chromoplexy). Using our systems, we aim to model and decipher the occurrence of these secondary events, including chromoplexic events.