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Cancer Cell Biology Programme

Seve-Ballesteros Foundation Brain Tumour Group

Group Leader:  Massimo Squatrito
Research highlights
Next generation glioma mouse models

A decade of studies has underlined the complexity of the glioma genome, however, the functional significance of the vast majority of the genetic alterations remains elusive. Understanding the genetic events that lead to glioma formation and the mechanisms of resistance to therapy will be instrumental for the development of new treatment modalities for gliomas. To accurately reproduce the high genetic heterogeneity observed in glioma patients, we would have to recreate not just a handful of genetic alterations, but possibly dozens. The advent of the CRISPR/Cas genome editing technology has now made it possible to target almost any candidate cancer gene in the in vivo setting. We are actively working to develop the ‘next-generation’ glioma mouse models that more faithfully recapitulate in vivo the complexity of the GBM genome, with a particular interest in tumour suppressor genes and complex gene rearrangements.

Overcoming therapy resistance in GBM

The standard therapies for GBM patients, IR and temozolomide (TMZ), generate double-stranded DNA breaks (DSDBs), the most deleterious form of DNA damage. The DSDBs are then responsible for the initiation of the DNA Damage Response (DDR) and, consequently, the activation of DNA repair pathways and cell-cycle checkpoints. DDR signalling is a very intricate pathway and many of its elements can be altered in a given tumour patient, offering both challenges and opportunities from a treatment perspective. The most frequent resistance mechanism to TMZ treatment is the expression of the DNArepair gene O6 -methylguanine DNA methyltransferase (MGMT), however, other resistance mechanisms have still to be identified.

Through a variety of genetic approaches (Haploid cells transposone mutagenesis, gRNA and shRNA screenings) we have identified the main signalling pathways that mediate resistance to TMZ. We are currently performing a series of synthetic lethality screenings in order to bypass these mechanisms of resistance.