Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model

Abstract

Tumorigenesis is a complex process, which requires alterations in several tumor suppressor or oncogenes. Here, we use a Drosophila tumor model to identify genes, which are specifically required for tumor growth. We found that reduction of phosphoinositide 3-kinase (PI3K) activity resulted in very small tumors while only slightly affecting growth of wild-type tissue. The observed inhibition on tumor growth occurred at the level of cell-cycle progression. We conclude that tumor cells become dependent on PI3K function and that reduction of PI3K activity synthetically interferes with tumor growth. The results presented here broaden our insights into the intricate mechanisms underling tumorigenesis and illustrate the power of Drosophila genetics in revealing weak points of tumor progression.

Integrin signalling regulates YAP and TAZ to control skin homeostasis

“…By contrast, Drosophila stratified columnar epithelia such as the intestine require integrins, Src, EGFR and Yki to promote proliferation of basal layer stem/progenitor cells, suggesting that the regulatory connection between them described here is also conserved (Cordero et al, 2014;Jiang et al, 2011;Kohlmaier et al, 2015;Lin et al, 2013;Shaw et al, 2010;Staley and Irvine, 2010;Xu et al, 2011). Furthermore, ectopic activation of Src, EGFR, PI3K or Yki in simple columnar imaginal discs is sufficient to induce overproliferation of cells, whereas loss of PI3K or Yki strongly impairs imaginal disc tumour formation (Doggett et al, 2011;Enomoto and Igaki, 2013;Fernandez et al, 2014;Herranz et al, 2012Herranz et al, , 2014Strassburger et al, 2012;Willecke et al, 2011).…”

Drosophila in cancer research: to boldly go where no one has gone before

“…These methods are already fruitful in exploring the interactions among cancer mutations, and between cell populations that mimic the tumor microenvironment. In this issue of Oncogene, Willecke et al (2011) describe the implementation of a novel genetic screen in Drosophila to identify genes required for tumor growth in vivo. This report illustrates the power of using Drosophila to perform systematic genome-wide genetic screens in complex genetic backgrounds and for the resulting data to inform our understanding of transformation and metastasis in human systems.…”

“…Further, libraries of transgenic Drosophila stocks that conditionally express interfering double-stranded RNAs (dsRNAi) targeting almost every gene in the Drosophila genome are now available (Dietzl et al, 2007; National Institute of Genetics, NIG-FLY). Willecke et al (2011) used these emerging genetic techniques to build an elegant system to screen for genes required for tumor growth in vivo. Such screens in complex genetic backgrounds can now be performed systematically in Drosophila on a genome-wide scale, rapidly informing our understanding of complex diseases such as cancer.…”

“…In all other cells, Gal80 inhibits Gal4 and consequently Ras V12 and GFP are not expressed. Adapted from Pagliarini and Xu (2003 Willecke et al (2011) used the Gal4-UAS system to build a fly stock that expressed the yeast transcription factor Gal4 in developing eye tissues and also carried Gal4 responsive UAS-transgenes expressing Ras V12 , GFP and dsRNAi targeting discs large (dlg), which encodes a scaffold protein that binds to Scrib and is required for cell polarity (Humbert et al, 2008). In these flies, Gal4 drives the expression of the UAS-Ras V12 , -dlg RNAi and -GFP transgenes, thereby inducing tumor phenotypes similar to the Ras V12 -scrib tumors described by the Richardson and Xu groups.…”

“…In these flies, Gal4 drives the expression of the UAS-Ras V12 , -dlg RNAi and -GFP transgenes, thereby inducing tumor phenotypes similar to the Ras V12 -scrib tumors described by the Richardson and Xu groups. To create a viable stock containing all these genetic elements, Willecke et al (2011) These examples illustrate the use of Drosophila as a model system to perform complex genetic manipulations in vivo. The Willecke strategy in particular allows systematic screening of a library of UAS-RNAi stocks in a complex tumor model in vivo.…”