A neurogenic model of adult brain cancer in Drosophila

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive adult brain tumour, with a subset of cells identified as GBM stem cells (GSCs). These cells are undifferentiated, highly tumourigenic and play an essential role in malignancy. Alterations of the tumour suppressor gene PTEN are prevalent in primary GBM. Recently, PTEN loss has been associated with the deregulation of a specific molecular axis, responsible for the maintenance of GSCs in mammals. This axis consists of PTEN, aPKC and Lethal giant larvae (Lgl). PTEN loss of function promotes aPKC activation, which in turn leads to Lgl inhibition, known to support GSC maintenance. METHODS: Despite the anatomical divergence between humans and fly, several aspects of brain development are conserved. In particular, type II neuroblasts (NBs) have a lineage similar as that of the mammalian neural stem cells. We developed a Drosophila brain cancer model based on the deregulation the of PTEN/aPKC/Lgl axis. These proteins are involved in the growth and polarity of NBs and, for this reason, their genetic manipulation may represent a good starting point for investigating the origin of GBM. Dysfunction of this axis has been specifically induced in type II NBs by the use of a binary expression system that allows gene manipulation in defined cell types.. RESULTS: Here we show that PTEN mutation impacts on aPKC and Lgl protein levels also in Drosophila. Perturbations of this conserved axis in the fly brain cause an accumulation of type II NBs, which form tumours that persist and keep growing in the adult, leading the animals to premature death. CONCLUSIONS: Our neurogenic model of adult brain cancer summarises many traits typical of human brain cancers. We aim at restricting and possibly identifying the NB lineage the most susceptible to PTEN inactivation, in order to gain more knowledge on the origin and biology of GBM.