Soft-tissue sarcomas (STSs) are rare mesenchymal tumors that arise from muscle, fat and connective tissue. Currently, over 75 subtypes of STS are recognized. The rarity and heterogeneity of patient samples complicate clinical investigations into sarcoma biology. Model organisms might provide traction to our understanding and treatment of the disease. Over the past 10 years, many successful animal models of STS have been developed, primarily genetically engineered mice and zebrafish. These models are useful for studying the relevant oncogenes, signaling pathways and other cell changes involved in generating STSs. Recently, these model systems have become preclinical platforms in which to evaluate new drugs and treatment regimens. Thus, animal models are useful surrogates for understanding STS disease susceptibility and pathogenesis as well as for testing potential therapeutic strategies.

There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery.

Helicobacter pylori, a common pathogen that causes chronic gastritis and cancer, has evolved to establish persistent infections in the human stomach. Epidemiological evidence suggests that H. pylori with both highly active vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA), the major virulence factors, has an advantage in adapting to the host environment. However, the mechanistic relationship between VacA and CagA remains obscure. Here, we report that CagA interferes with eukaryotic endocytosis, as revealed by genome-wide screening in yeast. Moreover, CagA suppresses pinocytic endocytosis and the cytotoxicity of VacA in gastric epithelial cells without affecting clathrin-dependent endocytosis. Our data suggest that H. pylori secretes VacA to attack distant host cells while injecting CagA into the gastric epithelial cells to which the bacteria are directly attached, thereby protecting these attached host cells from the cytotoxicity of VacA and creating a local ecological niche. This mechanism might allow H. pylori to balance damage to one population of host cells with the preservation of another, allowing for persistent infection.

In Belgium a unique science prize, the InBev-Baillet Latour Health Prize, recognizes someone whose pioneering research has led to the practical application of fundamental research. The international jury chose Professor Stephen O’Rahilly as the 2010 recipient for his work that identified a number of genetic factors that contribute to obesity. His research changed the way that many people think about the causes of obesity and altered the way that many patients are treated for obesity-related disease.Metabolic diseases, such as obesity and type 2 diabetes, are a growing concern associated with a variety of symptoms including cardiovascular disease, neurological degeneration and some types of cancer. Dr O’Rahilly was the first person to show that a single or very small number of genetic variations can predispose individuals to obesity. He has helped identify many crucial genetic elements that contribute to the complex pathophysiological mechanisms of metabolic diseases. The list of implicated genes that he has linked to metabolic disease continues to grow, but already includes genes that regulate appetite, insulin synthesis, insulin sensitivity and the cellular response to insulin. He and his colleagues have not only showed that a deficiency of leptin, an adipose-derived hormone, predisposed individuals to obesity but they also helped patients normalize their body weight through the administration of recombinant leptin. His work also shows that genetic factors predispose certain individuals to type 2 diabetes. Dr O’Rahilly’s integration of patient information with mouse studies has illuminated new inroads to treating metabolic disease.DMM would like to congratulate its founding editor, Dr Stephen O’Rahilly for this recognition of his contributions to science and medicine.

Understanding liver development should lead to greater insights into liver diseases and improve therapeutic strategies. In a forward genetic screen for genes regulating liver development in zebrafish, we identified a mutant--oliver--that exhibits liver-specific defects. In oliver mutants, the liver is specified, bile ducts form and hepatocytes differentiate. However, the hepatocytes die shortly after their differentiation, and thus the resulting mutant liver consists mainly of biliary tissue. We identified a mutation in the gene encoding translocase of the outer mitochondrial membrane 22 (Tomm22) as responsible for this phenotype. Mutations in tomm genes have been associated with mitochondrial dysfunction, but most studies on the effect of defective mitochondrial protein translocation have been carried out in cultured cells or unicellular organisms. Therefore, the tomm22 mutant represents an important vertebrate genetic model to study mitochondrial biology and hepatic mitochondrial diseases. We further found that the temporary knockdown of Tomm22 levels by morpholino antisense oligonucleotides causes a specific hepatocyte degeneration phenotype that is reversible: new hepatocytes repopulate the liver as Tomm22 recovers to wild-type levels. The specificity and reversibility of hepatocyte ablation after temporary knockdown of Tomm22 provides an additional model to study liver regeneration, under conditions where most hepatocytes have died. We used this regeneration model to analyze the signaling commonalities between hepatocyte development and regeneration.

Despite improved understanding of the pathobiology of pulmonary arterial hypertension (PAH), it remains a severe and progressive disease, usually culminating in right heart failure, significant morbidity and early mortality. Over the last decade, some major advances have led to substantial improvements in the management of PAH. Much of this progress was pioneered by work in animal models. Although none of the current animal models of pulmonary hypertension (PH) completely recapitulate the human disease, they do provide insight into the cellular pathways contributing to its development and progression. There is hope that future work in model organisms will help to define its underlying cause(s), identify risk factors and lead to better treatment of the currently irreversible damage that results in the lungs of afflicted patients. However, the difficulty in defining the etiology of idiopathic PAH (IPAH, previously known as primary pulmonary hypertension) makes this subset of the disease particularly difficult to model. Although there are some valuable existing models that are relevant for IPAH research, the area would value from the development of new models that more closely mimic the clinical pathophysiology of IPAH.

Pathogen diversification can alter infection virulence, which in turn drives the evolution of host immune diversification, resulting in countermeasures for survival in this arms race. Somatic recombination of the immunoglobulin gene family members is a very effective mechanism to diversify antibodies and T-cell receptors that function in the adaptive immune system. Although mechanisms to diversify innate immune genes are not clearly understood, a seemingly unlikely source for insight into innate immune diversification may be derived from the purple sea urchin, which has recently had its genome sequenced and annotated. Although there are many differences, some characteristics of the sea urchin make for a useful tool to understand the human immune system. The sea urchin is phylogenetically related to humans although, as a group, sea urchins are evolutionarily much older than mammals. Humans require both adaptive and innate immune responses to survive immune challenges, whereas sea urchins only require innate immune functions. Genes that function in immunity tend to be members of families, and the sea urchin has several innate immune gene families. One of these is the Sp185/333 gene family with about 50 clustered members that encode a diverse array of putative immune response proteins. Understanding gene diversification in the Sp185/333 family in the sea urchin may illuminate new mechanisms of diversification that could apply to gene families that function in innate immunity in humans, such as the killer immunoglobulin-like receptor genes.

Autosomal dominant polycystic kidney disease (ADPKD) results from loss-of-function mutations in PKD1 or PKD2. The products of these genes, the polycystins PC-1 and PC-2, form a transmembrane channel that is necessary for flow sensing by renal cilia. In C. elegans, the polycystin orthologs LOV-1 and PKD-2 function in sensory neurons that mediate male mating behavior. Here, we report that the novel single-pass membrane protein CWP-5 is necessary for polycystin signaling during the response step of mating behavior. As with the polycystins, CWP-5 localizes to neuronal cilia; this localization requires LOV-1. The response defect of cwp-5 mutants does not appear to result from disruption of ciliogenesis or polycystin localization. Instead, genetic and behavioral analyses indicate that CWP-5 represses a previously undescribed antagonistic effect of the polycystins on sensory function. Although cwp-5 does not have a primary-sequence ortholog in vertebrates, it has intriguing parallels with the autosomal recessive PKD gene FPC (also known as PKHD1). Together, this study identifies a new component of C. elegans polycystin signaling, demonstrates that the polycystins have a latent capacity to hinder sensory transduction, and suggests that aberrant functions of the polycystins could contribute to the pathogenesis of PKD.

The endometrium, the specialized lining of the uterus, is the most common target tissue for cancers of the female reproductive tract. Early-stage endometrial cancers can be cured, but patients diagnosed with late-stage disease have a median survival of less than a year, and the effectiveness of treatment has not improved in the last 30 years. Animal models of endometrial cancer have been developed but, to date, none has solely endometrial-specific expression, a prerequisite for the precisely targeted genetic manipulation that is needed to study the molecular biology of the disease. The tumor suppressor gene LKB1 is frequently mutated in human cancers, and decreased LKB1 expression in endometrial cancer correlates with a higher grade and stage. LKB1 encodes a protein kinase that normally restrains the activation of the AMP-dependent kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway, whose deregulation is important for the initiation and progression of many cancers. Inhibitors of the mTOR protein itself, such as temsirolimus, a rapamycin derivative, have been used to treat renal cell and endometrial cancers, although only a minority of patients respond.This paper addresses the dual need for the development of a new model system for endometrial cancer and the study of LKB1-driven neoplasia. The authors identify an endometrial-specific promoter and use it to drive expression of Cre recombinase in transgenic mice, meaning that any gene of interest can be manipulated in the endometrial epithelium. They use these mice to explore the consequences of deletion of the mouse Lkb1 gene in endometrial cancer. Aggressive, invasive endometrial cancers with an early onset and 100% incidence developed, resulting in extrauterine tumor spread and death. The effects of loss of Lkb1 were partially reversed by blocking the resulting hyperactivation of the AMPK-mTOR pathway using the mTOR inhibitor rapamycin. Prolonged rapamycin administration not only slowed the growth of early tumors, but also resulted in shrinkage of advanced tumors, and significant clinical remissions.Lkb1 is a remarkably potent endometrial tumor suppressor, as its inactivation is sufficient to drive the rapid formation of invasive and lethal endometrial cancers. In addition to developing a new model for endometrial cancer, this is the first study demonstrating that rapamycin is an effective agent against invasive cancers that are driven by Lkb1 deficiency. The model described here can be used to further dissect the initiation and progression of endometrial cancer, and the data also provide a rationale for the setup of clinical trials to test the idea that LKB1 deficiency is a sensitive indicator of responsiveness to anticancer therapies using rapamycin analogs.