Home > Research > Scientific Programmes: Cancer Cell Biology Programme > Seve-Ballesteros Foundation Brain Tumour Group

Cancer Cell Biology Programme

Seve-Ballesteros Foundation Brain Tumour Group

Group Leader:  Massimo Squatrito
Research highlights
Precision glioma mouse models

It has gradually been established that the vast majority of human tumours are extraordinarily heterogeneous at a genetic level. To accurately recapitulate this complexity, it is now evident that in vivo animal models of cancer will need to recreate not just a handful of simple genetic alterations, but possibly dozens and increasingly intricate. In our laboratory, by combining the RCAS/TVA and CRISPR/Cas9 systems, we have developed novel mouse models for in vivo somatic genome editing that allow the targeting of specific cell types with definite genetic alterations in order to generate precision tumour models.

We have shown that somatic deletion in neural stem cells (NSCs) of a variety of known tumour suppressor genes (Trp53, Cdkn2a and Pten), in combination with the expression of an oncogene driver, leads to glioblastoma (GBM) formation. Using this approach, we are currently performing in vivo guide RNA (gRNA) screenings to identify novel tumour suppressor genes that contribute to gliomagenesis.

Gene fusions have been documented as cancer-drivers for more than three decades, providing valuable insights into the tumorigenesis process. The occurrence and importance of gene fusions in glioma has been appreciated only recently − largely due to high-throughput technologies − and gene fusions have been indicated as one of the major genomic abnormalities in GBM. By simultaneous delivery of pairs of gRNAs we generated different gene fusions, either by chromosomal deletion (Bcan-Ntrk1) or by chromosomal translocation (Myb-Qk), and we have shown that they have transforming potential in vitro and in vivo.

Lastly, using homology-directed-repair (HDR), we also produced tumours carrying the BRAF V600E mutation, frequently identified in a variety of subtypes of gliomas.

In summary, we have developed an extremely powerful and versatile mouse model for in vivo somatic genome editing, which will elicit the generation of more accurate cancer models particularly appropriate for pre-clinical testing.