Why your microbiome shouldn't drink

Researchers from the University of California at San Diego have shown how chronic alcohol consumption led to changes in the microbiome that furthered the development of cirrhosis. Alcohol is directly damaging to the liver, but previous work had also shown that the chance of developing cirrhosis could be lowered by manipulating the gut microbiome. In the new study, the team showed that lower levels of specific antimicrobial proteins due to alcohol consumption led to overgrowth of bacteria on the mucosa of the small intestine, compromising the integrity of the mucosa and leading to liver damage. The scientists concluded that "alcohol appears to impair control of the mucosa-associated microbiota, and subsequent breach of the mucosal barrier facilitates progression of alcoholic liver disease." They published their results in the Feb. 10, 2016, online issue of Cell Host & Microbe.

Tumors: shooting themselves in the foot

Scientists at Harvard Medical School and the University of New Mexico have reported that circulating tumor cells might be manipulated to fight the cancers they are derived from. Recent research has shown that tumors engage in a process of self-seeding, that is, circulating tumor cells preferentially home to existing metastases of the primary tumors they are derived from. In their work, the authors made use of this phenomenon by genetically engineering tumor cells to express tumor necrosis factor (TNF), which, as its name suggests, can kill tumor cells. When they were injected into the bloodstream of tumor-bearing mice, such cells homed to primary tumors and metastases, and induced "massive tumor cell apoptosis." In addition, "tumor-cell-mediated delivery avoids or minimizes common side effects often associated with TNF-based therapy, such as acute inflammation and weight loss. Our study provides proof of concept that genetically modified circulating tumor cells may serve as targeted vectors to deliver anticancer agents," the authors concluded. The study appeared in the Feb. 8, 2016, online issue of the Proceedings of the National Academy of Sciences.

FGF fights fat, in liver

Researchers from the Salk Institute for Biological Studies and the Dutch University of Groningen have gained new insights into the effects of fibroblast growth factor (FGF) on nonalcoholic fatty liver disease (NAFLD). FGF acts downstream from peroxisome proliferator-activated receptor-gamma (PPAR-gamma), whose agonists are classical diabetes treatments but can have serious side effects. In their experiments, the authors looked at two different models of liver disease in mice and found that treatment with recombinant FGF improved inflammation in both models, but fat buildup in the liver was prevented in only one of the two models. The authors concluded that FGF affected fat catabolism and inflammation via independent mechanisms, and that "in addition to its potent glucose-lowering and insulin sensitizing effects, rFGF1 could be therapeutically effective in the treatment of NAFLD." They published their results in the Feb. 8, 2016, online issue of the Proceedings of the National Academy of Sciences.

KRAS partner in crime

Scientists from the Spanish Centro Nacional de Investigaciones Oncológicas have identified the receptor tyrosine kinase discoidin domain receptor 1 (DDR1) as a mediator of growth in very early KRAS-mutant lung tumors. KRAS is mutated in many tumors, including a fraction of lung adenocarcinomas. KRAS has proven highly challenging to target directly, and so the authors looked for co-occurring mutations in mouse tumors that were very early stage, consisting of fewer than 500 cells at the time of analysis. They identified DDR1 as a kinase that was expressed in a subset of these very early tumors. Moreover, that subset had an overall gene expression profile that was similar to that of KRAS-driven advanced human lung adenocarcinomas. Blocking DDR1 stopped tumor initiation and progression, and combining DDR1 inhibition with also inhibiting Notch induced regression of KRAS-driven tumors. The authors published their results in the Feb. 8, 2016, issue of Nature Medicine.

Cytochromes and cancer

Scientists from the German Cancer Research Center and the Heidelberg Institute for Stem Cell Technology and Experimental Medicine have shown that the cytochrome P450 enzyme family plays a role in both pre-existing and acquired drug resistance in pancreatic cancers. Cytochrome P450 is a family of enzymes that metabolize many drugs. In their experiments, the authors developed patient-derived pancreatic cancer models, and identified biomarkers that could help classify patient samples into three previously described pancreatic cancer subtypes. They then showed that patients' form of one particular cytochrome enzyme, CYP3A5 affected "both basal and acquired resistance to small-molecule drugs in [pancreatic cancer]. Because CYP3A5 is dispensable for normal physiology, its inhibition in cancers is a promising therapeutic option," the authors concluded, though they also cautioned that designing specific inhibitors could prove challenging given the structural similarity of different members of the cytochrome family. They published their results in the Feb. 8, 2016, issue of Nature Medicine.

What drives T cells to attack in T1D

Type I diabetes occurs when helper T cells instigate an autoimmune response to pancreatic beta cells, but to date, the actual epitopes those cells respond to have not been identified. Now, researchers from the University of Colorado at Denver have shown that the cells recognize hybrid insulin peptides that were formed when insulin precursor peptides bonded with other peptides present in beta cells. Proinsulin is known to be an important target for autoimmune T cells that cause type I diabetes, but why the immune system would lose tolerance to proinsulin has not been obvious. The authors used a combination of proteomics approaches and T cells from a mouse model of type I diabetes to identify the specific targets of helper T cells in diabetic mice, and found that targets consisted of fused peptides of proinsulin and other peptides. Since such peptides are not part of the body's regular repertoire, the findings provide one mechanism of how T cells could break tolerance to proinsulin. The findings appeared in the Feb. 12, 2016, issue of Science.

Engineering synthetic cells

Researchers from the University of California at San Francisco have developed a method to engineer cells to respond to non-natural inputs with non-natural processes by using the developmental regulatory protein Notch. Notch receptors are very straightforward in how they respond to their natural ligands. When stimulated by an extracellular signal, they release a transcription factor that is bound to their intracellular domain, which then goes on to modulate gene expression programs. In their work, the authors engineered synthetic Notch receptors that could respond to environmental signals of the authors' choosing, and also engineered the intracellular domain to contain different transcription factors, leading to cells that could respond to novel stimulatory inputs with novel transcriptional outputs. In a separate paper out of the laboratory of the same senior author, researchers described using the method to develop a CAR T cell that was active only when both of two antigens were present. The findings could expand the repertoire of T cells, and synthetic biology more generally. They appeared in the Jan. 28, 2016, issue of Cell.

The long and short of chronic GLP agonists

Researchers from the University of Miami Miller School of Medicine and the Swedish Karolinska Institutet have found that long-term treatment with Saxenda (liraglutide, Novo Nordisk A/S) compromised pancreatic beta cell function in a humanized mouse model. Liraglutide is one of a class of relatively novel diabetes drugs, the GLP agonists. Because these drugs are relatively new, information about their chronic use is now beginning to emerge, and there have been some concerns about serious complications with long-term use. In their work, the authors treated humanized mice with high doses of liraglutide for long periods of time. While treatment initially improved blood glucose control, that control deteriorated progressively after about 200 days of treatment. "These findings raise concern about the chronic potentiation of beta cell function through incretin mimetic therapy in diabetes," the authors concluded. Their work appeared in the Feb. 11, 2016, online issue of Cell Metabolism.

Nanoparticle reduces targeted drug toxicity

Scientists from Bind Therapeutics Inc. and Astrazeneca plc have shown that a nanoparticle formulation of the aurora B kinase inhibitor AZD8211 had better efficacy and lower toxicity in multiple preclinical tumor models than a prodrug of the same inhibitor. Much of the focus in nanoparticles for cancer drug delivery has been on nontargeted agents, because of their high toxicity. However, certain classes of targeted agents, including the Aurora kinase inhibitors, are also beset by toxicity concerns. In their work, the authors showed that at least in the case of AZD8211, these concerns could be addressed by a nanoparticle formulation in preclinical models. The editor's summary for the paper stated that "a phase I trial is the next step for this nanomedicine, and additional preclinical studies will reveal whether such nanoformulations can improve the tolerability and efficacy of the broader class of molecularly targeted cancer therapeutics, including cell cycle inhibitors." The results were published in the Feb. 10, 2016, issue of Science Translational Medicine.

Leptin: A weight loss tail

Researchers from the Swedish Lund University have gained new insights into the hormone leptin and its effects on weight. Leptin regulates appetite, and leptin signaling is deregulated in obese individuals. Current theory holds that leptin affects weight via effects on energy-burning brown fat, but in their work, the authors found no such effect. Instead, leptin appeared to affect the body temperature set point, and affected body temperature and the energy expenditure required to by regulating heat loss through the tail in mice. The authors concluded that "the present studies should, therefore, help in directing further efforts concerning leptin action into its effects on the mechanisms of body temperature control." Their work appeared in the Feb. 11, 2016, online issue of Cell Reports.

By Anette Breindl, Senior Science Editor