No abstract

Among extant reptiles only two lineages are known to have evolved venom delivery systems, the advanced snakes and helodermatid lizards (Gila Monster and Beaded Lizard). Evolution of the venom system is thought to underlie the impressive radiation of the advanced snakes (2,500 of 3,000 snake species). In contrast, the lizard venom system is thought to be restricted to just two species and to have evolved independently from the snake venom system. Here we report the presence of venom toxins in two additional lizard lineages (Monitor Lizards and Iguania) and show that all lineages possessing toxin-secreting oral glands form a clade, demonstrating a single early origin of the venom system in lizards and snakes. Construction of gland complementary-DNA libraries and phylogenetic analysis of transcripts revealed that nine toxin types are shared between lizards and snakes. Toxinological analyses of venom components from the Lace Monitor Varanus varius showed potent effects on blood pressure and clotting ability, bioactivities associated with a rapid loss of consciousness and extensive bleeding in prey. The iguanian lizard Pogona barbata retains characteristics of the ancestral venom system, namely serial, lobular non-compound venom-secreting glands on both the upper and lower jaws, whereas the advanced snakes and anguimorph lizards (including Monitor Lizards, Gila Monster and Beaded Lizard) have more derived venom systems characterized by the loss of the mandibular (lower) or maxillary (upper) glands. Demonstration that the snakes, iguanians and anguimorphs form a single clade provides overwhelming support for a single, early origin of the venom system in lizards and snakes. These results provide new insights into the evolution of the venom system in squamate reptiles and open new avenues for biomedical research and drug design using hitherto unexplored venom proteins.

Squamate reptiles number approximately 8000 living species and are a major component of the world's terrestrial vertebrate diversity. However, the established relationships of the higher-level groups have been questioned in recent molecular analyses.Here we expand the molecular data to include DNA sequences, totaling 6192 base pairs (bp), from nine nuclear protein-coding genes (C-mos, RAG1, RAG2, R35, HOXA13, JUN, α-enolase, amelogenin and MAFB) for 19 taxa representing all major lineages. Our phylogenetic analyses yield a largely resolved phylogeny that challenges previous morphological analyses and requires a new classification. The limbless dibamids are the most basal squamates. Of the remaining taxa (Bifurcata), the gekkonids form a basal lineage. The Unidentata, squamates that are neither dibamids nor gekkonids, are divided into the Scinciformata (scincids, xantusiids, and cordylids) and the Episquamata (remaining taxa). Episquamata includes Laterata (Teiformata, Lacertiformata, and Amphisbaenia, with the latter two joined in Lacertibaenia) and Toxicofera (iguanians, anguimorphs and snakes). Our results reject several previous hypotheses that identified either the varanids, or a burrowing lineage such as amphisbaenians or dibamids, as the closest relative of snakes. Our study also rejects the monophyly of both Scleroglossa and Autarchoglossa, because Iguania, a species-rich lineage (ca. 1440 sp.), is in a highly nested position rather than being basal among Squamata. Thus iguanians should not be viewed as representing a primitive state of squamate evolution but rather a specialized and successful clade combining lingual prehension, dependence on visual cues, and ambush foraging mode, and which feeds mainly on prey avoided by other squamates. Molecular time estimates show that the Triassic and Jurassic (from 250 to 150 Myr) were important times for squamate evolution and diversification.

Pancreatic ductal adenocarcinoma is one of the most intractable and fatal cancer. The decreased blood vessel density displayed by this tumor not only favors its resistance to chemotherapy but also participates in its aggressiveness due to the consequent high degree of hypoxia. It is indeed clear that hypoxia promotes selective pressure on malignant cells that must develop adaptive metabolic responses to reach their energetic and biosynthetic demands. Here, using a well-defined mouse model of pancreatic cancer, we report that hypoxic areas from pancreatic ductal adenocarcinoma are mainly composed of epithelial cells harboring epithelial-mesenchymal transition features and expressing glycolytic markers, two characteristics associated with tumor aggressiveness. We also show that hypoxia increases the "glycolytic" switch of pancreatic cancer cells from oxydative phosphorylation to lactate production and we demonstrate that increased lactate efflux from hypoxic cancer cells favors the growth of normoxic cancer cells. In addition, we show that glutamine metabolization by hypoxic pancreatic tumor cells is necessary for their survival. Metabolized glucose and glutamine converge toward a common pathway, termed hexosamine biosynthetic pathway, which allows O-linked N-acetylglucosamine modifications of proteins. Here, we report that hypoxia increases transcription of hexosamine biosynthetic pathway genes as well as levels of O-glycosylated proteins and that O-linked N-acetylglucosaminylation of proteins is a process required for hypoxic pancreatic cancer cell survival. Our results demonstrate that hypoxia-driven metabolic adaptive processes, such as high glycolytic rate and hexosamine biosynthetic pathway activation, favor hypoxic and normoxic cancer cell survival and correlate with pancreatic ductal adenocarcinoma aggressiveness.pancreas | malignancy | metabolism | glutamate N inety-five percent of patients with pancreatic cancer harbor tumors classified as pancreatic ductal adenocarcinoma (PDAC). Commonly described as a silent killer regarding its late diagnosis, PDAC is noted for its aggressiveness and its intrinsic resistance to standard chemotherapy. This specificity is probably due to a low vascular density and a prominent nontumoral cell compartment (stroma), which impact on intratumoral perfusion, therapeutic delivery, and patient outcome (1). Indeed, PDAC is characterized by numerous and severe hypoxic regions (2), a feature that has been proven to be correlated with tumor aggressiveness and poor prognosis compared with well-oxygenated tumors (3). Moreover, combined with hypoxia, the subsequent nutrient-devoid environment provides physiological selective pressure promoting expansion of the most aggressive malignant cells, particularly those acquiring mutations in genes encoding tumor suppressor protein p53 (TP53) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog protein (KRAS) (4, 5), two of the main mutations present in PDAC patients. Regarding such statements, it appears relevant to deeply explore consequ...