Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator PGC1α suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1α is down-regulated in prostate cancer and associated to disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1α opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1α activates an Oestrogen-related receptor alpha (ERRα)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1α-ERRα pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment.

The Hedgehog signalling pathway is crucial for development, adult stem cell maintenance, cell migration and axon guidance in a wide range of organisms. During development, the Hh morphogen directs tissue patterning according to a concentration gradient. Lipid modifications on Hh are needed to achieve graded distribution, leading to debate about how Hh is transported to target cells despite being membrane-tethered. Cytonemes in the region of Hh signalling have been shown to be essential for gradient formation, but the carrier of the morphogen is yet to be defined. Here we show that Hh and its co-receptor Ihog are in exovesicles transported via cytonemes. These exovesicles present protein markers and other features of exosomes. Moreover, the cell machinery for exosome formation is necessary for normal Hh secretion and graded signalling. We propose Hh transport via exosomes along cytonemes as a significant mechanism for the restricted distribution of a lipid-modified morphogen.

Localized expression of the transforming growth factor-beta (TGF-beta) homologue decapentaplegic (dpp) is crucial for Drosophila wing development. Here we show that spalt and spalt-related (sal and salr), two closely related genes that encode transcription factors, are expressed in response to dpp in a central territory of the wing imaginal disc, where they are required for the patterning of the wing. They are among the first identified elements that act downstream of dpp in wing development. The phenotypic consequences of misexpression of sal and salr suggest that an important outcome of dpp activity is the subdivision of the wing disc into territories smaller than lineage compartments, through the regulation of transcription-factor-encoding genes such as sal and salr.

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation1,2. Here we show that mTORC1 regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. Through the use of integrative metabolomics in a mouse model3 and human biopsies4 of prostate cancer, we identified alterations in tumours impacting on the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation was validated in murine and human cancer specimens. AMD1 was upregulated in prostate cancer specimens with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus5 exhibited a predominant decrease in AMD1 immunoreactivity that was associated to a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

Spalt and Spalt-related encode conserved Zn-finger proteins that mediate the function of the TGF-beta molecule Decapentaplegic during the positioning of veins in the Drosophila wing. Here we show that Spalt and Spalt-related regulate the vein-specific expression of the transcription factors of the knirps and iroquois gene complexes, delimiting their domains of expression in the wing pouch. The effects of spalt/spalt-related mutations on knirps and iroquois expression are cell-autonomous, suggesting that they could be direct. The regulation of iroquois involves transcriptional repression by Spalt and Spalt-related, whereas the regulation of knirps involves a combination of transcriptional activation and repression mediated by the same genes. We suggest that the regulation of the iroquois and knirps gene complexes by Spalt and Spalt-related translates the Decapentaplegic morphogenetic gradient into precisely spaced pattern elements.

The genes of the spalt (sal) family play fundamental roles during animal development. The two members of this family in Drosophila, spalt (sal) and spalt-related (salr) encode Znfinger transcription factors that link the Decapentaplegic (Dpp)/BMP signalling pathway to the patterning of the wing. They are regulated by the Dpp pathway in the wing disc, and they were shown to mediate some of the morphogenetic activities of the Dpp/BMP4 secreted ligand. The sal genes were initially found by virtue of mutations that produce homeotic transformations in the head and tail of the Drosophila embryo. Since then, a number of other requirements have been associated to these genes in Drosophila, including morphogenesis of the respiratory system, cell fate specification of sensory organs and the differentiation of several photoreceptor cells, among others. Vertebrate sal orthologues (spalt-like/sall) have also important developmental roles during neural development and organogenesis, and at least two human sall genes are linked to the genetic diseases Townes Brocks Syndrome (TBS; SALL1 ) and Okihiro Syndrome (OS; SALL4). In this review, we will summarize the main characteristics of the sall genes and proteins, pointing out to the similarities in their developmental roles during Drosophila and vertebrate development.

Animals have a determined species-specific body size that results from the combined action of hormones and signaling pathways regulating growth rate and duration. In Drosophila, the steroid hormone ecdysone controls developmental transitions, thereby regulating the duration of the growth period. Here we show that ecdysone promotes the growth of imaginal discs in mid-third instar larvae, since imaginal discs from larvae with reduced or no ecdysone synthesis are smaller than wild type due to smaller and fewer cells. We show that insulin-like peptides are produced and secreted normally in larvae with reduced ecdysone synthesis, and upstream components of insulin/insulin-like signaling are activated in their discs. Instead, ecdysone appears to regulate the growth of imaginal discs via Thor/4E-BP, a negative growth regulator downstream of the insulin/insulin-like growth factor/Tor pathways. Discs from larvae with reduced ecdysone synthesis have elevated levels of Thor, while mutations in Thor partially rescue their growth. The regulation of organ growth by ecdysone is evolutionarily conserved in hemimetabolous insects, as shown by our results obtained using Blattella germanica. In summary, our data provide new insights into the relationship between components of the insulin/insulin-like/Tor and ecdysone pathways in the control of organ growth.

In the Drosophila wing blade, Decapentaplegic (Dpp), a member of the transforming growth factor-␤ superfamily, controls the patterning of the veins, through the regulation of different downstream genes (for comprehensive reviews on the Dpp pathway and vein patterning, see refs. 1 and 2). Briefly, secreted Dpp forms a gradient and binds to membrane receptors that propagate the signal via phosphorylation of Mothers against dpp (Mad). This protein binds to Medea (Med), and the Mad-Med complexes translocate to the nucleus, where they regulate transcription. Brinker (Brk), a repressor of Dpp target genes, is expressed in the most lateral parts of the wing blade, while it is repressed in the central part of the wing by Schnurri (Shn), a zinc finger transcription factor that forms complexes with Mad and Med (3). Thus, Brk repression depends on Dpp, and, at the same time, it represses Dpp target genes. It has been proposed that Brk displaces the activator Mad from target sequences (4-6).The role of Dpp on wing and vein patterning is mainly mediated by the Spalt (Sal) zinc finger transcription factors (7,8). The expression of sal in the wing blade is strictly dependent on Dpp signaling and occurs in a broad central domain that covers from the L2 provein until the anterior limit of the L5 provein (Fig. 1C). Thus, dpp mutant discs, or clones of cells mutant for the Dpp receptor Thick veins (Tkv), completely lose sal expression (7, 9, 10). Two main inputs of Dpp signaling have been identified affecting sal expression. First, Brk represses sal expression, and Dpp is necessary to repress brk expression in the central domain of the wing by means of Shn-Mad-Med complexes. A second input of Dpp is necessary to reach normal levels of sal expression and occurs independently of Brk. Thus, tkv͞brk and mad͞brk double mutant clones, which lack at the same time the repressor (Brk) and the activators of the pathway (Tkv or Mad), still express sal, although at levels lower than normal (11-13). These observations indicate that some activators of sal expression are operative in the absence of Dpp signaling. It has been proposed that this activation is provided by Vestigial (Vg), a factor essential for wing and haltere disc development (14-16). Vg forms complexes with Scalloped (Sd) that bind DNA in a sequence-specific manner to regulate the expression of downstream genes (17)(18)(19).sal genes show a complex pattern of expression regulated by independent enhancer regions (20, 21). Here, we characterize a sal wing blade-specific enhancer that includes all the information needed to generate the sal expression domain in the wing. This enhancer contains Brk binding sequences, responsible for the repression of sal in the lateral regions of the wing, and activator sequences that drive reporter gene expression in the sal domain. Because activation and repression regions do not overlap, a mechanism based on Mad displacement by Brk is, in this case, unlikely. Med and Sd bind to the activation region, although mutations in their binding sites do not...