Centrosome Dysfunction in Drosophila Neural Stem Cells Causes Tumors that Are Not Due to Genome Instability

Abstract

Genome instability (GI) and centrosomal alterations are common traits in human cancer [1, 2]. It is suspected that centrosome dysfunction may cause tumors by bringing about GI, but direct experimental proof is still lacking [3]. To explore the possible functional link between centrosome function and overgrowth, we have assayed the tumorigenic potential of a series of mutants that affect different centrosomal proteins in Drosophila. We have found that a significant number of such mutant conditions are tumorigenic in larval brain tissue, where self-renewing asymmetric division of neural stem cells is frequent, but not in symmetrically dividing epithelial cells. We have also found that mutations that increase GI without causing centrosome dysfunction are not tumorigenic in our assay. From these observations, we conclude that the tumors caused by centrosome dysfunction cannot be explained solely by the resulting genome instability. We propose that such tumors might be caused by impaired asymmetric division of neural stem cells [4]. These results show that centrosome loss, far from being innocuous, is a potentially dangerous condition in flies.

Tumor suppressor roles of CENP-E and Nsl1 inDrosophilaepithelial tissues

“…These structures have proved useful as model systems to elucidate the molecular mechanisms underlying tumorigenic growth, 18,19 including the contribution of CIN to tumorigenesis. 10 The depletion of genes involved in the spindle assembly checkpoint (bub3, rough deal), spindle assembly (abnormal spindle [asp]), chromatin condensation (orc2), and cytokinesis (diaphanous [dia])-all known to recapitulate the genomic defects most frequently associated with human cancer, including chromosome rearrangements and aneuploidy 9 -induce CIN and PCD in wing imaginal disc cells.…”

“…8 In the last few years, the contribution of CIN to tumorigenesis has also been analyzed in Drosophila cancer models. CIN per se does not induce tumorigenesis in brain 9 or epithelial tissues. 10 Since aneuploidy can be detrimental for cells, additional mutations might contribute to the survival of these cells and to CIN-induced tumorigenesis.…”

A new Augmin subunit, Msd1, demonstrates the importance of mitotic spindle-templated microtubule nucleation in the absence of functioning centrosomes

“…Interestingly, although acentrosomal flies have been shown to be viable, the lack of astral MTs during the asymmetric cell divisions of stem cells in these mutants results in a randomization of the plane of cytokinesis with regard to asymmetrically localized fate determinants (Giansanti et al 2001;Megraw et al 2001;Basto et al 2006). Larval brains from such acentrosomal mutants often develop tumors in an allograft transplantation assay, suggesting a link between loss of centrosomes and tumor formation (Castellanos et al 2008). Our study therefore raises the intriguing possibility that global inhibition of Augmin function would prevent cell division only in cells possessing tumorogenic activity brought about through an absence of functioning centrosomes, while having minimal effect on all other cells.…”

SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress

“…Mice heterozygous for PLK4 (PLK4 þ / À ) spontaneously develop liver and lung tumours, whereas PLK4 homozygous null mice are embryonic lethal 17 . Furthermore, overexpression of PLK4 promotes tumorigenesis in Drosophila 18,19 . Therefore, PLK4 activity must be adequately controlled to maintain centrosome integrity and to prevent carcinogenesis.…”