A neurogenic model of adult brain cancer in Drosophila

Glioblastoma multiforme (GBM) is the most common brain cancer of the adult, with a very poor prognosis. It is characterised by a subset of undifferentiated and highly tumourigenic cells, called GBM stem cells (GSC), responsible for cancer aggressiveness and relapse. Despite the obvious anatomical differences between humans and flies, the structural and functional analogy of the respective nervous systems and the conservation of the cellular and molecular aberrations at the basis of the disease make Drosophila an excellent model for human brain cancer. Inactivation of the tumour suppressor gene PTEN is frequent in primary GBMs, resulting in the inhibition of the polarity protein Lgl1 due to aPKC hyperactivation. Dysregulation of this molecular axis is sufficient to reprogramme human neural progenitors into GSC. First, we have proved that the PTEN/aPKC/Lgl axis is conserved in Drosophila. Second, we have disrupted this conserved axis specifically in type II neuroblasts, a cell population with a lineage comparable to that of mammalian neural stem cells, obtaining aggressive tumours which persist and keep growing in the adult, leading the animals to premature death. This neurogenic model recapitulates many phenotypical traits of human brain cancers, included high proliferation rate, accumulation of undifferentiated neural cells, local invasiveness and genetic instability. With the aim to identify crucial gene expression aberrations of this devastating disease, we are going to analyse fly brain cancers by RNAseq. Following data analysis, the most relevant targets will undergo functional characterisation in patient-derived GMB cell lines showing an impairment of the PTEN/aPKC/Lgl molecular axis. The manipulated cell lines will also be injected intracranially in SCID mice to observe major changes in cancer growth and aggressiveness.