Regulation of ROS signaling by TIGAR induces cancer-modulating responses in the tumor microenvironment.

The consequences of reactive oxygen species (ROS) in cancer cells are complex and have been shown to both promote and retard tumorigenesis in different models. In mouse models of pancreatic ductal adenocarcinoma (PDAC), loss of the antioxidant defense gene results in both a reduction in the development of early pancreatic intraepithelial neoplasia and an increase in invasive and metastatic capacity, accompanied by decreased survival of mice lacking pancreatic TIGAR. We previously demonstrated that increased ROS following loss of TIGAR promotes various cancer cell-intrinsic changes that contribute to metastatic capacity, including epithelial to mesenchymal transition, enhanced migration and invasion, and an increase in ERK signaling.

The dietary sweetener sucralose is a negative modulator of T cell-mediated responses.

Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years. Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners. In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation.

The role of ROS in tumour development and progression.

Eukaryotic cells have developed complex systems to regulate the production and response to reactive oxygen species (ROS). Different ROS control diverse aspects of cell behaviour from signalling to death, and deregulation of ROS production and ROS limitation pathways are common features of cancer cells. ROS also function to modulate the tumour environment, affecting the various stromal cells that provide metabolic support, a blood supply and immune responses to the tumour.

The impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells.

Serine is a non-essential amino acid that is critical for tumour proliferation and depletion of circulating serine results in reduced tumour growth and increased survival in various cancer models. While many cancer cells cultured in a standard tissue culture medium depend on exogenous serine for optimal growth, here we report that these cells are less sensitive to serine/glycine depletion in medium containing physiological levels of metabolites. The lower requirement for exogenous serine under these culture conditions reflects both increased de novo serine synthesis and the use of hypoxanthine (not present in the standard medium) to support purine synthesis.

Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer.

The TIGAR protein has antioxidant activity that supports intestinal tissue repair and adenoma development. Using a pancreatic ductal adenocarcinoma (PDAC) model, we show that reactive oxygen species (ROS) regulation by TIGAR supports premalignant tumor initiation while restricting metastasis. Increased ROS in PDAC cells drives a phenotypic switch that increases migration, invasion, and metastatic capacity.

Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization.

Cancer metastasis depends on cell survival following loss of extracellular matrix attachment and dissemination through the circulation. The metastatic spread can be enhanced by the clustering of detached cancer cells and increased antioxidant defense. Here, we link these responses by describing how cell clustering limits reactive oxygen species (ROS).

Corrigendum: Modulating the therapeutic response of tumours to dietary serine and glycine starvation.

This corrects the article DOI: 10.1038/nature22056.

Development of an inducible mouse model of iRFP713 to track recombinase activity and tumour development in vivo.

While the use of bioluminescent proteins for molecular imaging is a powerful technology to further our understanding of complex processes, fluorescent labeling with visible light fluorescent proteins such as GFP and RFP suffers from poor tissue penetration and high background autofluorescence. To overcome these limitations, we generated an inducible knock-in mouse model of iRFP713. This model was used to assess Cre activity in a Rosa Cre-ER background and quantify Cre activity upon different tamoxifen treatments in several organs.

Modulating the therapeutic response of tumours to dietary serine and glycine starvation.

The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis, many others rely on exogenous serine for optimal growth.

Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine.

Reactive oxygen species (ROS) participate in numerous cell responses, including proliferation, DNA damage, and cell death. Based on these disparate activities, both promotion and inhibition of ROS have been proposed for cancer therapy. However, how the ROS response is determined is not clear.

iRFP is a real time marker for transformation based assays in high content screening.

Anchorage independent growth is one of the hallmarks of oncogenic transformation. Here we show that infrared fluorescent protein (iRFP) based assays allow accurate and unbiased determination of colony formation and anchorage independent growth over time. This protocol is particularly compatible with high throughput systems, in contrast to traditional methods which are often labor-intensive, subjective to bias and do not allow further analysis using the same cells.

TIGAR, TIGAR, burning bright.

Cancers cells shift their metabolism towards glycolysis in order to help them support the biosynthetic demands necessary to sustain cell proliferation and growth, adapt to stress and avoid excessive reactive oxygen species (ROS) accumulation. While the p53 tumor suppressor protein is known to inhibit cell growth by inducing apoptosis, senescence and cell cycle arrest, recent studies have found that p53 is also able to influence cell metabolism. TIGAR is a p53 target that functions as a fructose-2,6-bisphosphatase, thereby lowering glycolytic flux and promoting antioxidant functions.

Metabolic regulation by p53 family members.

The function of p53 is best understood in response to genotoxic stress, but increasing evidence suggests that p53 also plays a key role in the regulation of metabolic homeostasis. p53 and its family members directly influence various metabolic pathways, enabling cells to respond to metabolic stress. These functions are likely to be important for restraining the development of cancer but could also have a profound effect on the development of metabolic diseases, including diabetes.

Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death.

The p53-inducible protein TIGAR (Tp53-induced Glycolysis and Apoptosis Regulator) functions as a fructose-2,6-bisphosphatase (Fru-2,6-BPase), and through promotion of the pentose phosphate pathway, increases NADPH production to help limit reactive oxygen species (ROS). Here, we show that under hypoxia, a fraction of TIGAR protein relocalized to mitochondria and formed a complex with hexokinase 2 (HK2), resulting in an increase in HK2 activity. Mitochondrial localization of TIGAR depended on mitochondrial HK2 and hypoxia-inducible factor 1 (HIF1α) activity.

High density spectral beam combination with spatial chirp precompensation.

A method for spectral combination of lasers with extremely high spectral density is introduced, enabling greater than 80% and theoretically approaching 100% spectral density utilization with no degradation in beam quality. Experiments demonstrating the utility of our method are described, cumulating in a demonstration of a compact, packaged laser with photonic-crystal-fiber-rod amplifiers at 0.5-MW peak power and 0.

The role of p53 in glucose metabolism.

The p53 protein functions to prevent tumour development by inhibiting the outgrowth of stressed or damaged cells. In addition to well established functions to block cell proliferation, recent studies have revealed a role for p53 in the regulation of pathways involved in glucose metabolism. The metabolic functions of p53 resist the shift to glycolysis that is characteristically seen in cancers, and also help cells adapt to and survive limited periods of metabolic stress.

Modulation of intracellular ROS levels by TIGAR controls autophagy.

The p53-inducible TIGAR protein functions as a fructose-2,6-bisphosphatase, promoting the pentose phosphate pathway and helping to lower intracellular reactive oxygen species (ROS). ROS functions in the regulation of many cellular responses, including autophagy--a response to stress conditions such as nutrient starvation and metabolic stress. In this study, we show that TIGAR can modulate ROS in response to nutrient starvation or metabolic stress, and functions to inhibit autophagy.

Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage.

Despite the importance of Mcl-1, an anti-apoptotic Bcl-2 family member, in the regulation of apoptosis, little is known regarding its role in nervous system development and injury-induced neuronal cell death. Because germline deletion of Mcl-1 results in peri-implantation lethality, we address the function of Mcl-1 in the nervous system using two different conditional Mcl-1 mouse mutants in the developing nervous system. Here, we show for the first time that Mcl-1 is required for neuronal development.

Diffractive-optics-based beam combination of a phase-locked fiber laser array.

A diffractive optical element (DOE) is used as a beam combiner for an actively phase-locked array of fiber lasers. Use of a DOE eliminates the far-field sidelobes and the accompanying loss of beam quality typically observed in tiled coherent laser arrays. Using this technique, we demonstrated coherent combination of five fiber lasers with 91% efficiency and M2=1.

Mitofusin 2 protects cerebellar granule neurons against injury-induced cell death.

Of the GTPases involved in the regulation of the fusion machinery, mitofusin 2 (Mfn2) plays an important role in the nervous system as point mutations of this isoform are associated with Charcot Marie Tooth neuropathy. Here, we investigate whether Mfn2 plays a role in the regulation of neuronal injury. We first examine mitochondrial dynamics following different modes of injury in cerebellar granule neurons.