Failure of the PTEN/aPKC/Lgl Axis Primes Formation of Adult Brain Tumours inDrosophila

Abstract

Different regions in the mammalian adult brain contain immature precursors, reinforcing the concept that brain cancers, such as glioblastoma multiforme (GBM), may originate from cells endowed with stem-like properties. Alterations of the tumour suppressor gene PTEN are very common in primary GBMs. Very recently, PTEN loss was shown to undermine a specific molecular axis, whose failure is associated with the maintenance of the GBM stem cells in mammals. This axis is composed of PTEN, aPKC, and the polarity determinant Lethal giant larvae (Lgl): PTEN loss promotes aPKC activation through the PI3K pathway, which in turn leads to Lgl inhibition, ultimately preventing stem cell differentiation. To find the neural precursors responding to perturbations of this molecular axis, we targeted different neurogenic regions of the Drosophila brain. Here we show that PTEN mutation impacts aPKC and Lgl protein levels also in Drosophila. Moreover, we demonstrate that PI3K activation is not sufficient to trigger tumourigenesis, while aPKC promotes hyperplastic growth of the neuroepithelium and a noticeable expansion of the type II neuroblasts. Finally, we show that these neuroblasts form invasive tumours that persist and keep growing in the adult, leading the affected animals to untimely death, thus displaying frankly malignant behaviours.

Melatonin improves cognitive behavior, oxidative stress, and metabolism in tumor‐prone lethal giant larvae mutant of Drosophila melanogaster

“…Deficiencies in cognition are common in a wide range of cancers such as brain and breast cancers (Pendergrass et al, 2018). Mutation in lgl is known to cause asymmetric cell division of neuroblastoma cells and induce tumor(s) formation in the brain (Paglia et al, 2017). Additionally, lgl mutant flies do develop oxidative stress during tumorigenesis (Goh et al, 2013;Herranz et al, 2016).…”

Drosophila melanogaster: A Model Organism to Study Cancer

“…Glioma stem cells divide asymmetrically under the guidance of cell polarity complexes that control the proper apical and basolateral polarization and cell division, a process that was originally identified in Drosophila and later confirmed for the mechanism driving differentiation in human glia for members of the Hugl-1/Llgl-1 complexes (Prehoda, 2009). We recently developed a neurogenic brain tumor model by impairing asymmetric cell division through the loss of function of lethal giant larvae ( lgl ) the Drosophila ortholog of Hugl-1 , in the type II NBs of the central brain (Paglia et al, 2017). In our model, PI3K activation mimics PTEN loss of function and hampers Lgl localization at the apical membrane by aPKC cortical recruitment (Paglia et al, 2017).…”

“…We recently developed a neurogenic brain tumor model by impairing asymmetric cell division through the loss of function of lethal giant larvae ( lgl ) the Drosophila ortholog of Hugl-1 , in the type II NBs of the central brain (Paglia et al, 2017). In our model, PI3K activation mimics PTEN loss of function and hampers Lgl localization at the apical membrane by aPKC cortical recruitment (Paglia et al, 2017). These data connect the function of HUGL-1 in the maintenance of glioma stem cells with the loss of function of the tumor suppressor PTEN (Gont et al, 2013) and together with those in glioma (Read et al, 2009) show a conserved function for PI3K and EGFR overexpression in these tumors recapitulating many features of the neurogenic subtype of human glioblastoma.…”

Drosophila Accessory Gland: A Complementary In Vivo Model to Bring New Insight to Prostate Cancer

“…Brain cancer is also widely studied in Drosophila . Several models have been made displaying different gene alterations: suppression of Brat expression to model glioma [ 148 ] and loss of function of lgl (lethal giant larvae) to model neurogenic brain tumors [ 149 ].…”