Genetic and molecular signature of glioblastoma stem-like cells

In the past years it was made a very huge effort to understand the genetic and molecular signatures of glioblastoma in order to improve targeted molecular therapy: but to date several things remain still unclear and new markers or new relationships have to been disclosed. Our aim is, therefore, to better clarify genetic signatures and pathways’ cross-talks in our glioblastoma-stem like cells model: actually we believe that these cells represent a real reservoir for the tumor of cells, which are able alone to maintain tumor growth, to give raise to a relapse and to determine radio- and chemo-resistance. First we presented a paper published in collaboration with our laboratory in 2012: in this study we found that the expression of MET oncogene was associated with a mesenchymal signature in our glioblastoma stem-like cells model and this expression is mutually exclusive with EGFR amplification; these cells also displayed different growth requirements in vitro and generated tumors with distinctive features in vivo; this suggested that MET could be a new target for therapy of a specific subset of GBMs (De Bacco et al 2012). Then we tried to better understand the possible cross-talk between EGFR and NF-kB signalling through a specific genetic signature disclosed in a precedent paper (Bredel et al 2011): a heterozygous deletion of NFKBIA gene, mutually exclusive with EGFR amplification. Surprisingly we found that this signature is a rare event in the primary tumor, but it is very frequent in our glioblastoma stem-like cells model in vitro and has also clear functional consequences. Our results raise the possibility that this deletion may be amplified in vitro, favored by the presence of EGF, mostly in that lines in which EGFR pathway is predominant; furthermore in these cells seems to be favored the constitutive active mutant of EGFR gene, EGFRvIII, probably in order to preserve EGFR-NF-kB axis. All these data suggest that our model is a much better system than serum-dependent cultures to study GBMs biology, bu at the same time various GSCs subgroups can be defined, that require both different factors to grow and also display different behaviours based on their genetic and molecular signatures.