Follow the evolution of the most widespread and aggressive brain tumor, glioblastoma, since the appearance of the first malignant cells, to pave the way for new treatment possibilities thanks to information on the development of the disease hitherto inaccessible with conventional experimental investigation techniques. All this is possible today thanks to a genetic ‘bar code’, which makes each tumor cell traceable and identifiable in time and space, so as to be able to follow the growth of the tumor mass step by step in an experimental mouse model. Thanks to advanced molecular biology techniques, such as transcriptome analysis, and computational models that have made it possible to simulate the evolution of the tumor on the computer, it has been possible to study the factors that influence its growth, such as the dynamics of diversification and selection that are established between the different clones of neoplastic cells. The innovative approach, which paves the way for new discoveries and possibilities in the research and treatment of glioblastoma, was developed by a team of researchers from the IRCCS San Martino Polyclinic Hospital in Genoa and the Department of Experimental Medicine of the University of Genoa, led by Prof Paolo Malatesta with the main contribution of Davide Ceresa. The results obtained are of such importance that they have just been published in Cancer Cell, one of the most important journals in the sector.
The glioblastoma
Glioblastoma, with about 1,500 new cases a year in Italy, is the most widespread brain tumor but also the most aggressive and still little known in the early stages. More frequent in men than in women (1.6 to 1) and in the age group between 45 and 75 years, it represents 45% of all tumors that develop in the brain. Ionizing radiations, such as X-rays and gamma rays, are recognized as a risk factor for the appearance of glioblastoma, which gives symptoms when the tumor mass, expanding, increases the pressure and dilates the blood vessels causing disturbances such as headaches of increasing intensity, vomiting, epileptic fits. “The therapy is extremely complex and, unfortunately, does not yet offer a definitive solution – observes Paolo Malatesta, co-author of the study, head of the Experimental Neuro-Oncology Program of the IRCCS San Martino of Genoa and professor of Molecular Biology at the University of Genoa – Currently , life expectancy for glioblastoma patients remains less than three years; however, the improvement of treatments could pass from a greater understanding of the development of the tumor, which is very heterogeneous from a cellular point of view and is little known in its initial stages”.
I study
In order to better understand the evolution of the disease from the earliest stages, the researchers at San Martino have developed a model of glioblastoma in which it was possible to trace every single neoplastic cell, in time and space. “We have introduced a sort of ‘bar code’ into the cells to be monitored, a particular string of DNA which, in addition to inducing the disease, also allows the tumor cells to be traced subsequently, following them thanks to sophisticated sequencing techniques – explains Davide Ceresa, co-author of the study and researcher at San Martino – By monitoring the evolution of neoplastic cells we have observed, for example, that within the first month of the mutation in a tumor sense most of the neoplastic cell clones disappear; by comparing the data on real tumor growth with those obtained thanks to computational models capable of simulating it in different scenarios and conditions, we verified the existence of very strong clonal selection in the early stages of glioblastoma development, which is also maintained in later stages. The dynamics of cellular competition therefore seem to play a primary role in determining the development of glioblastoma, even in more advanced stages of its growth. Basically, through sophisticated programs that allow us to simulate the growth of the tumor we were able to test our hypotheses by comparing the simulations with the real development of the neoplasm”.
Thanks to the analysis of the transcriptome, i.e. the set of genes transcribed, at the single cell level, the researchers have also identified the Myc gene, already known for its role in other tumors, as one of the major culprits of this process of clonal selection . “The decrease in Myc expression is sufficient to initiate competition dynamics between clones of malignant cells even in gliomas implanted in the brain of experimental animals, confirming their importance in the evolution of the disease – adds Malatesta -. This new approach, which combines innovative molecular biology techniques with the use of advanced computational models, has made it possible to gather important information on glioblastoma but above all paves the way for a better understanding of the development mechanisms of this tumour: fully understanding its evolution from the earliest stages was hitherto impossible, using conventional techniques that allow it to be studied only retrospectively, but clonal tracing and transcriptomic analysis techniques will now be able to provide new and important information that will serve to better understand and fight against it”.