PTEN: New form, new role

In the world of biotechnology, the protein PTEN comes up mainly because it is a tumor suppressor. But PTEN also has a wide variety of other biological functions. Researchers from Cornell University and the Chinese Peking University Health Sciences Center have added to that latter list, identifying a novel form of PTEN and showing that this form, which they named PTEN-alpha, plays a role in mitochondrial metabolism. The team first identified PTEN-alpha because it interacted with antibodies to PTEN, but was heavier than classical PTEN. They showed that PTEN-alpha induced ATP production in mitochondria, and that it interacted with classical PTEN to promote energy production. The authors concluded that "our studies demonstrate the importance of . . . alternative translation for generation of protein diversity in eukaryotic systems and provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes." They appeared in the April 24, 2014, advance online edition of Cell Metabolism.

Circulating cells give clues to metastases

Researchers from the Massachusetts Institute of Technology and the Broad Institute have developed a method to get information about the genomic state of cancer patients' metastases by capturing and sequencing circulating tumor cells (CTCs). Targeted treatments of cancer patients are most often based on biopsies taken from the primary tumor at the time of diagnosis. However, both that primary tumor and metastases may evolve significantly over time. However, neither repeated biopsies of the primary tumor nor comprehensive biopsies of metastases are reasonable in many cases. In their work, the authors developed a process to isolate, qualify and sequence whole exomes of circulating tumor cells with high fidelity. The authors concluded that "this study establishes a foundation for CTC genomics in the clinic," which is important for targeting. Scientifically, their process "may also enable longitudinal monitoring of the genetic state of disseminated cancer, revealing important insights in tumor evolution, metastatic dissemination and resistance to therapeutics." Their work appeared in the April 20, 2014, advance online edition of Nature Biotechnology.

Getting APP out of harm's way

Researchers from Columbia University Medical Center, Weill Cornell Medical College, and Brandeis University have managed to affect the processing of amyloid precursor protein (APP), which plays a role in Alzheimer's disease, through stabilizing the APP-processing retromer. Retromers are multiprotein complexes that transport proteins away from the endosome, and in neurons, one of the proteins they transport is APP. In their work, the authors used a mix of structural methods and screening to identify a small molecule that stabilized the retromer, which ultimately led to the shunting of APP away from endosomes, the place it is processed into A-beta. The work to date has all been done in cell culture, but the authors said that if the same principles hold in vivo, their findings could point to a new approach to lowering A-beta levels in Alzheimer's disease. Their work appeared in the April 20, 2014, issue of Nature Chemical Biology.

Stroke's effects on the BBB

Scientists from the Salk Institute and the University of California at Irvine have gained new insights into the details of how the blood-brain barrier (BBB) breaks down after a stroke, which might help develop therapeutics to prevent such a breakdown. How exactly stroke damages the BBB has been unknown to date, since the endothelial cells that line the blood vessels are not nearly as vulnerable as neurons themselves to stroke conditions. Endothelial cells mostly survive strokes, but the BBB nevertheless stops functioning. In their work, the authors showed that when they induced experimental strokes in animals, leakiness of the BBB was caused initially by increased transcytosis, an active transport process across the BBB. Only later, after about two days, did the tight junctions that link endothelial cells and provide a physical barrier become damaged. The findings appeared in the April 17, 2014, advance online issue of Neuron.

Take 2 aspirin and check your 15-PGDH levels

A team from Harvard University and Case Western Reserve University has discovered a gene whose levels determine who can use aspirin to protect themselves from colon cancer. Aspirin has been shown to protect against colon cancer in both epidemiological studies and randomized controlled trials, but susceptibility appears to vary widely. Molecularly, aspirin is protective by blocking a specific enzyme in the prostaglandin synthesis pathway, PTGS2. The authors hypothesized that individuals with low levels of another enzyme, 15-PGDH, might benefit from aspirin more because PTGS2 would naturally be more active in such individuals. Looking at epidemiological data of more than 100,000 individuals, they found that aspirin use was associated with a reduced risk of colon cancer in individuals with low levels of 15-PGDH, but not with high levels. 15-PGDH could serve as a biomarker to determine which subjects stand to benefit from preventive aspirin. The findings were published in the April 24, 2014, issue of Science Translational Medicine.

Down syndrome and ALL

Scientists from the Dana-Farber Cancer Institute and the Broad Institute have deciphered the molecular link between Down syndrome and B-cell acute lymphoblastic leukemia (B-ALL). Individuals with Down syndrome, who have an extra copy of chromosome 21, are at an enormously increased risk of developing B-ALL, an aggressive pediatric cancer. But given that trisomy-21 patients have extra copies of thousands of genes, as well as dysregulated gene expression across all chromosomes, the precise genetic issue leading to the link had not been worked out. In their work, the authors traced the link to overexpression of an epigenetic protein that affected the methylation status of a whole group of genes with a specific methylation tag, leading to their overexpression. The work appeared in the April 20, 2014, issue of Nature Genetics.

Stress, resilience . . .

Researchers from the Mount Sinai School of Medicine have managed to reverse depressive symptoms in an animal model by increasing, rather than suppressing, the activity of neurons whose firing leads to depressive symptoms. The authors first looked at the activity of neurons in a midbrain area known as the ventral tegmental area when animals were exposed to social stress, and found that those neurons increased their activity in animals who showed symptoms of depression and anxiety when they were exposed to social stress, but increased their activity even more in animals who were resilient to their negative experiences. The authors found that when they increased the activity of those neurons pharmacologically, the increased excitation ultimately set off compensatory inhibitory mechanisms, and the depression-like symptoms vanished. The authors said their results "indicate a potential therapeutic path of promoting natural resilience for depression treatment." They reported their results in the April 18, 2014, issue of Science.

. . . And eating

Researchers at the University of Texas Southwestern Medical Center have discovered new links between stress, depression, the hormone ghrelin and neurogenesis. Ghrelin is best known as a hormone that is involved in appetite regulation, but previous studies by the researchers had shown that ghrelin also had antidepressant effects, and that it mediated the antidepressant effects of calorie restriction. In their new work, the authors looked at ghrelin's relationship to the birth of new neurons in the brain. They found that ghrelin receptor knockout mice that are depression-prone when they are exposed to stress were impaired in their ability to generate new neurons. Treatment of those mice with a compound that stimulated neurogenesis, however, reversed the depressive effects of social stress. The authors concluded that their findings confirm the role of neurogenesis in resilience to depression, and suggest that their neuroprotective compound, P7C3, could represent a new approach to the treatment of depression. Their work appeared in the April 22, 2014, issue of Molecular Psychiatry.

Epigenetic approach to prostate cancer

Scientists at the University of Michigan have reported that in preclinical models, treating castration-resistant prostate cancer with a bromodomain inhibitor continued to be effective when the cancers had become resistant to androgen receptor-targeting approaches. Prostate cancers are driven by androgen receptor signaling and can initially be treated by blocking that signaling, but once they become resistant to androgen receptor blockers, as many do, such tumors are eventually fatal. In their experiments, the authors showed that resistant tumors could be treated by inhibiting the downstream epigenetic consequences of androgen receptor activation, by using the bromodomain inhibitors JQ1 or an analogue molecule. The authors said their studies show that "clinical evaluation of [bromodomain] inhibitors is warranted in [castration-resistant prostate cancer], either as monotherapy or in combination with second-generation anti-androgens." Their work appeared in the April 23, 2014, advance online issue of Nature.

Simplifying ASD alterations

A team from the multi-institutional Autism Genome Consortium has analyzed the copy number variations of roughly 2,500 families with autism spectrum disorders, and identified a "convergence of genes and pathways" that are deregulated in such disorders. Autism spectrum disorders are highly heritable, but sequencing of affected individuals has revealed a perplexing number of different genes that can be altered in many different ways. In their work, the authors sequenced autistic individuals and their parents, identifying both inherited and de novo variations, and subjected those data to a series of analyses to identify pathways whose functions those different genetic alterations might converge on. They were able to identify several such pathways. "Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants," the authors wrote, "converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation." Their work appeared in the April 24, 2014, issue of the American Journal of Human Genetics.

By Anette Breindl, Science Editor