Genomic instability has been observed in essentially all sporadic carcinomas. Here we use Drosophila epithelial cells to address the role of chromosomal instability in cancer development as they have proved useful for elucidating the molecular mechanisms underlying tumorigenic growth. We first show that chromosomal instability leads to an apoptotic response. Interestingly, this response is p53 independent, as opposed to mammalian cells, and depends on the activation of the c-Jun N-terminal kinase (JNK) signaling cascade. When prevented from undergoing programmed cell death (PCD), chromosomal instability induces neoplasic overgrowth. These tumor-like tissues are able to grow extensively and metastasize when transplanted into the abdomen of adult hosts. Detailed analysis of the tumors allows us to identify a delaminating cell population as the critical one in driving tumorigenesis. Cells loose their apicalbasal polarity, mislocalize DE-cadherin, and delaminate from the main epithelium. A JNK-dependent transcriptional program is activated specifically in delaminating cells and drives nonautonomous tissue overgrowth, basement membrane degradation, and invasiveness. These findings unravel a general and rapid tumorigenic potential of genomic instability, as opposed to its proposed role as a source of mutability to select specific tumor-prone aneuploid cells, and open unique avenues toward the understanding of the role of genomic instability in human cancer.

Chromosomal instability (CIN) is thought to be a source of mutability in cancer. However, CIN often results in aneuploidy, which compromises cell fitness. Here, we used the dosage compensation mechanism (DCM) of Drosophila to demonstrate that chromosome-wide gene dosage imbalance contributes to the deleterious effects of CIN-induced aneuploidy and its pro-tumorigenic action. We present evidence that resetting of the DCM counterbalances the damaging effects caused by CIN-induced changes in X chromosome number. Importantly, interfering with the DCM suffices to mimic the cellular effects of aneuploidy in terms of reactive oxygen species (ROS) production, JNK-dependent cell death, and tumorigenesis upon apoptosis inhibition. We unveil a role of ROS in JNK activation and a variety of cellular and tissue-wide mechanisms that buffer the deleterious effects of CIN, including DNA-damage repair, activation of the p38 pathway, and cytokine induction to promote compensatory proliferation. Our data reveal the existence of robust compensatory mechanisms that counteract CIN-induced cell death and tumorigenesis.

Multiple conserved mechanisms sense nutritional conditions and coordinate metabolic changes in the whole organism. We unravel a role for the Drosophila homolog of p53 (Dp53) in the fat body (FB; a functional analog of vertebrate adipose and hepatic tissues) in starvation adaptation. Under nutrient deprivation, FB-specific depletion of Dp53 accelerates consumption of major energy stores and reduces survival rates of adult flies. We show that Dp53 is regulated by the microRNA (miRNA) machinery and miR-305 in a nutrition-dependent manner. In well-fed animals, TOR signaling contributes to miR-305-mediated inhibition of Dp53. Nutrient deprivation reduces the levels of miRNA machinery components and leads to Dp53 derepression. Our results uncover an organism-wide role for Dp53 in nutrient sensing and metabolic adaptation and open up avenues toward understanding the molecular mechanisms underlying p53 activation under nutrient deprivation.

The gradient of Decapentaplegic (Dpp) in the Drosophila wing has served as a paradigm to characterize the role of morphogens in regulating patterning. However, the role of this gradient in regulating tissue size is a topic of intense debate as proliferative growth is homogenous. Here, we combined the Gal4/UAS system and a temperature-sensitive Gal80 molecule to induce RNAi-mediated depletion of dpp and characterise the spatial and temporal requirement of Dpp in promoting growth. We show that Dpp emanating from the AP compartment boundary is required throughout development to promote growth by regulating cell proliferation and tissue size. Dpp regulates growth and proliferation rates equally in central and lateral regions of the developing wing appendage and reduced levels of Dpp affects similarly the width and length of the resulting wing. We also present evidence supporting the proposal that graded activity of Dpp is not an absolute requirement for wing growth.DOI: http://dx.doi.org/10.7554/eLife.22013.001

Highlights d Wingless promotes tissue growth by restricting the activity of the TCF repressor form d Wingless and Dpp mediate the growth-promoting activities of signaling centers d Morphogens promote growth along distinct axes by using non-interchangeable mechanisms d The range of morphogen gradients and their combined activities regulate final tissue size

Highlights d CIN drives tissue invasiveness by promoting an amoeboidlike migratory behavior d The migratory behavior of aneuploid cells relies on activation of Myosin II by Rok d JNK promotes CIN-induced invasiveness through the Fos proto-oncogene d Ectopic Spitz/EGF drives CIN-induced invasiveness by inactivating Capicua

When exposed to DNA-damaging agents, components of the DNA damage response (DDR) pathway trigger apoptosis, cell cycle arrest and DNA repair. Although failures in this pathway are associated with cancer development, the tumor suppressor roles of cell cycle arrest and apoptosis have recently been questioned in mouse models. Using Drosophila epithelial cells that are unable to activate the apoptotic program, we provide evidence that ionizing radiation (IR)-induced DNA damage elicits a tumorigenic behavior in terms of E-cadherin delocalization, cell delamination, basement membrane degradation and neoplasic overgrowth. The tumorigenic response of the tissue to IR is enhanced by depletion of Okra/DmRAD54 or spnA/DmRAD51--genes required for homologous recombination (HR) repair of DNA double-strand breaks in G2--and it is independent of the activity of Lig4, a ligase required for nonhomologous end-joining repair in G1. Remarkably, depletion of Grapes/DmChk1 or Mei-41/dATR-genes affecting DNA damage-induced cell cycle arrest in G2--compromised DNA repair and enhanced the tumorigenic response of the tissue to IR. On the contrary, DDR-independent lengthening of G2 had a positive impact on the dynamics of DNA repair and suppressed the tumorigenic response of the tissue to IR. Our results support a tumor suppressor role of apoptosis, DNA repair by HR and cell cycle arrest in G2 in simple epithelia subject to IR-induced DNA damage.

the homeodomain proteins Engrailed (En) and Invected are expressed in the posterior (P) compartment, where they are required to repress Ci expression (Eaton and Kornberg, 1990) and relieve Ci-mediated repression of hh (Bejarano and Milan, 2009). PcG proteins help to maintain the repression of hh expression in A cells whereas TrxG proteins contribute to maintaining the expression of hh in P cells (Bejarano and Milan, 2009;Chanas and Maschat, 2005). Notch activity at the dorsal-ventral (DV) compartment boundary has also been reported to participate in the regulation of hh expression; however, the mechanistic basis behind this is uncertain (Bejarano and Milan, 2009). Although communication between the hh-ME and those cis-enhancers that integrate positional information conferred by the activities of Ci, En and Notch has been proposed as a way to initiate and maintain the transcriptional state of hh in P cells, the identity of these enhancers and the proposed communication remain elusive.Here, we have isolated a 4.3-kb cis-regulatory region that recapitulates hh expression in the P compartment of the wing primordium. This fragment includes the previously defined hh-ME and a nearby enhancer (termed C enhancer) that responds to En, Ci and Notch and drives gene expression to a thin stripe in the P compartment that corresponds to the DV compartment boundary. We present evidence that the ME maintains the initial transcriptional Development 138, 3125-3134 (2011) SUMMARYTrithorax-group and Polycomb-group proteins interact with chromosomal elements, termed PRE/TREs, to ensure stable heritable maintenance of the transcriptional state of nearby genes. Regulatory elements that bind both groups of proteins are termed maintenance elements (MEs). Some of these MEs maintain the initial activated transcriptional state of a nearby reporter gene through several rounds of mitosis during development. Here, we show that expression of hedgehog in the posterior compartment of the Drosophila wing results from the communication between a previously defined ME and a nearby cisregulatory element termed the C enhancer. The C enhancer integrates the activities of the Notch and Hedgehog signalling pathways and, from the early wing primordium stage, drives expression to a thin stripe in the posterior compartment that corresponds to the dorsal-ventral compartment boundary. The ME maintains the initial activated transcriptional state conferred by the C enhancer and contributes to the expansion, by growth, of its expression domain throughout the posterior compartment. Communication between the ME and the C enhancer also contributes to repression of gene expression in anterior cells. Most interestingly, we present evidence that enhancers and MEs of different genes are interchangeable modules whose communication is involved in restricting and expanding the domains of gene expression. Our results emphasize the modular role of MEs in regulation of gene expression within growing tissues.