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Simple Summary: Cancer genomics and transcriptomics have revealed genes and pathways altered in several cancers. These studies have provided valuable information about cancer cells, their origin, oncogenic processes, and signaling pathways. An emerging challenge is to further characterize activity levels and interactions of pathways to develop a deeper understanding of how specific alterations in these interactions promote tumor growth. Drosophila with its sophisticated genetics has proved valuable in studying cooperative oncogenesis. Using Drosophila tumor models, we report a tumor cell-specific network comprising four pathways. We show that Wingless and effector caspase Dronc direct a signal amplification loop involving JNK and Hippo-effector Yorkie (Yki). Our studies provide evidence from in vivo studies regarding the organization of tumor-promoting oncogenic pathways, which may be useful in developing precise and effective approaches for pathway inhibition. These pathways are evolutionarily conserved from flies to humans, suggesting that findings from flies can be extrapolated to mammalian cancers. Cancer cells expand rapidly in response to altered intercellular and signaling interactions to achieve the hallmarks of cancer. Impaired cell polarity combined with activated oncogenes is known to promote several hallmarks of cancer, e.g., activating invasion by increased activity of Jun N-terminal kinase (JNK) and sustained proliferative signaling by increased activity of Hippo effector Yorkie (Yki). Thus, JNK, Yki, and their downstream transcription factors have emerged as synergistic drivers of tumor growth through pro-tumor signaling and intercellular interactions like cell competition. However, little is known about the signals that converge onto JNK and Yki in tumor cells and enable tumor cells to achieve the hallmarks of cancer. Here, using mosaic models of cooperative oncogenesis (RasV12,scrib−) in Drosophila, we show that RasV12,scrib− tumor cells grow through the activation of a previously unidentified network comprising Wingless (Wg), Dronc, JNK, and Yki. We show that RasV12,scrib− cells show increased Wg, Dronc, JNK, and Yki signaling, and all these signals are required for the growth of RasV12,scrib− tumors. We report that Wg and Dronc converge onto a JNK–Yki self-reinforcing positive feedback signal-amplification loop that promotes tumor growth. We found that the Wg–Dronc–Yki–JNK molecular network is specifically activated in polarity-impaired tumor cells and not in normal cells, in which apical-basal polarity remains intact. Our findings suggest that the identification of molecular networks may provide significant insights into the key biologically meaningful changes in signaling pathways and paradoxical signals that promote tumorigenesis. [ABSTRACT FROM AUTHOR]

Despite the conservation of genetic machinery involved in eye development, there is a strong diversity in the placement of eyes on the head of animals. Morphogen gradients of signaling molecules are vital to patterning cues. During Drosophila eye development, Wingless (Wg), a ligand of Wnt/Wg signaling, is expressed anterolaterally to form a morphogen gradient to determine the eye-versus head-specific cell fate. The underlying mechanisms that regulate this process are yet to be fully understood. We characterized defective proventriculus (dve) (Drosophila ortholog of human SATB1), a K50 homeodomain transcription factor, as a dorsal eye gene, which regulates Wg signaling to determine eye versus head fate. Across Drosophila species, Dve is expressed in the dorsal head vertex region where it regulates wg transcription. Second, Dve suppresses eye fate by down-regulating retinal determination genes. Third, the dve-expressing dorsal head vertex region is important for Wg-mediated inhibition of retinal cell fate, as eliminating the Dve-expressing cells or preventing Wg transport from these dve-expressing cells leads to a dramatic expansion of the eye field. Together, these findings suggest that Dve regulates Wg expression in the dorsal head vertex, which is critical for determining eye versus head fate. Gain-of-function of SATB1 exhibits an eye fate suppression phenotype similar to Dve. Our data demonstrate a conserved role for Dve/SATB1 in the positioning of eyes on the head and the interocular distance by regulating Wg. This study provides evidence that dysregulation of the Wg morphogen gradient results in developmental defects such as hypertelorism in humans where disproportionate interocular distance and facial anomalies are reported. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.07.030 Byline: Sarah M. Oros, Meghana Tare, Madhuri Kango-Singh, Amit Singh Keywords: Drosophila eye; Dorso-ventral eye patterning; Pannier; GATA-1; Retinal determination; Homothorax; Teashirt; Wg Signaling Abstract: Axial patterning is crucial for organogenesis. During Drosophila eye development, dorso-ventral (DV) axis determination is the first lineage restriction event. The eye primordium begins with a default ventral fate, on which the dorsal eye fate is established by expression of the GATA-1 transcription factor pannier (pnr). Earlier, it was suggested that loss of pnr function induces enlargement in the dorsal eye due to ectopic equator formation. Interestingly, we found that in addition to regulating DV patterning, pnr suppresses the eye fate by downregulating the core retinal determination genes eyes absent (eya), sine oculis (so) and dacshund (dac) to define the dorsal eye margin. We found that pnr acts downstream of Ey and affects the retinal determination pathway by suppressing eya. Further analysis of the 'eye suppression' function of pnr revealed that this function is likely mediated through suppression of the homeotic gene teashirt (tsh) and is independent of homothorax (hth), a negative regulator of eye. Pnr expression is restricted to the peripodial membrane on the dorsal eye margin, which gives rise to head structures around the eye, and pnr is not expressed in the eye disc proper that forms the retina. Thus, pnr has dual function, during early developmental stages pnr is involved in axial patterning whereas later it promotes the head specific fate. These studies will help in understanding the developmental regulation of boundary formation of the eye field on the dorsal eye margin. Article History: Received 13 June 2010; Revised 26 July 2010; Accepted 27 July 2010

eyeless (ey) is a key regulator of the eye development pathway in Drosophila. Ectopic expression of ey can induce the expression of several eye-specification genes (eya, so, and dac) and induce eye formation in multiple locations on the body. However, ey does not induce eye formation everywhere where it is ectopically expressed, suggesting that EY needs to collaborate with additional factors for eye induction. We examined ectopic eye induction by EY in the wing disc and found that eye induction was spatially restricted to the posterior compartment and the anterior-posterior (A/P) compartmental border, suggesting a requirement for both HH and DPP signaling. Although EY in the anterior compartment induced dpp and dac, these were not sufficient for eye induction. Coexpression experiments show that EY needs to collaborate with high level of HH and DPP to induce ectopic eye formation. Ectopic eye formation also requires the activation of an eye-specific enhancer of the endogenous hh gene. Keywords: Drosophila; Eye induction; Signaling; Pax6; ey; hh; dpp

A new water-soluble zinc(II) porphyrin has been synthesized and characterized by high resolution mass spectroscopy, elemental analysis, and electronic absorption spectroscopy. The zinc(II) porphyrin (ZnPor) is designed with three Nmethylated pyridyl groups at the meso-positions to make the compound water soluble. In addition, a meso-pentafluorophenyl substituent has been incorporated to enhance the excited state lifetime of the porphyrin. The addition of zinc(II) into the porphyrin core lends itself to longer excited lifetimes as well as the ability to coordinate to DNA bases exposed in the major groove. The ZnPor and its free-base analog (FBPor) demonstrate high binding affinity to calf thymus DNA (ctDNA) with binding constants greater than 100000 M-1. Both porphyrins show the ability to photonick DNA when irradiated within the photodynamic therapy window (600-850 nm); however, ZnPor shows enhanced photoreactions and the ability to cause double strand breaks. Under hypoxic conditions only ZnPor is capable of causing single strand breaks when irradiated with visible light. Both ZnPor and FBPor are nontoxic to the lung cancer cell line A549 in the dark at concentrations as high as 100 μM but show cytotoxicity to A549 cells at concentrations as low as 75 nM when irradiated with visible light. Studies of the ZnPor in Drosophila melanogaster indicate statistically insignificant toxicity when compared to control at concentrations well above the light-induced toxicity levels. Evidence for localization of ZnPor in the nuclei of the Drosophila salivary gland cells suggests a mechanism for cellular transport, which may prove beneficial in PDT treatment. [ABSTRACT FROM AUTHOR]