A neurogenic model of adult brain cancer in Drosophila

Abstract

Primary brain cancers are characterised by high cellular heterogeneity, with a subset of undifferentiated and highly tumourigenic cells responsible for cancer aggressiveness and relapse. Despite 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. Early inactivation of the tumour suppressor gene PTEN is frequent in primary glioblastoma, the most aggressive form of adult brain cancer whose origin is still controversial. This results in the inhibition of the polarity protein Lgl due to aPKC hyper-activation. Dysregulation of this molecular axis is sufficient to reprogramme human neural progenitors into cancer stem cells. After having confirmed that the PTEN/aPKC/Lgl axis is conserved in Drosophila, we have disrupted it in type II neuroblasts, a cell population with a lineage comparable to that of mammalian neural stem cells, obtaining aggressive tumours that persist and keep growing in the adult, leading the animals to premature death. This neurogenic model recapitulates many phenotypic traits of human brain cancers, included high proliferation rate, accumulation of undifferentiated neural cells and local invasiveness