Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment.DOI: http://dx.doi.org/10.7554/eLife.19375.001

This study investigates whether laminarin (β1-3,β1-6-glucan), a polysaccharide from seaweed, exhibits beneficial properties for human health by analysing its effects on intestinal parameters. Anaerobic batch culture fermenters were used for the screening of the in vitro utilization of laminarin by the human gut microflora through the monitoring of biochemical and microbiological parameters. Additionally, the influence of laminarin ingestion on the composition of intestinal mucus (neutral mucins, sialomucins and sulphomucins) was studied in rats. Laminarin was almost totally (more than 90% used) fermented after 24 h of incubation with human intestinal bacteria. It was not selectively used by bifidobacteria and lactobacilli, but increased the production of propionate and butyrate. Variations of mucus composition were observed in jejunum, ileum, caecum and colon, both in lumen content and in intestinal wall, of rats after ingestion of this polysaccharide. Due to its effects on mucus composition, laminarin could influence the adherence and the translocation of bacteria across the epithelial wall. In conclusion, laminarin seems to be a modulator of the intestinal metabolism by its effects on mucus composition, intestinal pH and short chain fatty acid (SCFA) production, especially butyrate.

Dietary fibres consist of edible plant polysaccharides that are resistant to digestion and absorption in the human small intestine but undergo complete or partial fermentation in the colon. Seaweeds, notably Laminaria spp, are particularly rich in polysaccharides resistant to hydrolysis in the upper gastrointestinal tract and are, in consequence, considered as dietary fibres. Most of the carbohydrates from Laminaria spp are thought to be indigestible by humans. The main storage polysaccharide of these algae is laminarin, a β-polymer of glucose. The aims of this work were, on the one hand, to compare various methods of extraction of laminarin by partial characterisation of the product obtained and, on the other hand, to study the fate of this polysaccharide and its effects in the gastrointestinal tract in order to determine its potential as a dietary fibre in human nutrition. Among four methods tested to extract laminarin, the best appeared to be a hot HCl-based method. Human digestive enzymes did not hydrolyse laminarin, so this polysaccharide can be considered as a dietary fibre. After ingestion by rats, this polysaccharide was not found in faeces of these animals. It did not increase the intestinal transit and stool output in vivo, but it increased the contractile response of the stomach to acetylcholine in vitro.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism.

BackgroundHigh-mobility group box 1 (HMGB1) is a multifunctional redox-sensitive protein involved in various intracellular (eg, chromatin remodeling, transcription, autophagy) and extracellular (inflammation, autoimmunity) processes. Regarding its role in cancer development/progression, paradoxical results exist in the literature and it is still unclear whether HMGB1 mainly acts as an oncogene or a tumor suppressor.MethodsHMGB1 expression was first assessed in tissue specimens (n=359) of invasive breast, lung and cervical cancer and the two distinct staining patterns detected (nuclear vs cytoplasmic) were correlated to the secretion profile of malignant cells, patient outcomes and the presence of infiltrating immune cells within tumor microenvironment. Using several orthotopic, syngeneic mouse models of basal-like breast (4T1, 67NR and EpRas) or non-small cell lung (TC-1) cancer, the efficacy of several HMGB1 inhibitors alone and in combination with immune checkpoint blockade antibodies (anti-PD-1/PD-L1) was then investigated. Isolated from retrieved tumors, 14 immune cell (sub)populations as well as the activation status of antigen-presenting cells were extensively analyzed in each condition. Finally, the redox state of HMGB1 in tumor-extruded fluids and the influence of different forms (oxidized, reduced or disulfide) on both dendritic cell (DC) and plasmacytoid DC (pDC) activation were determined.ResultsAssociated with an unfavorable prognosis in human patients, we clearly demonstrated that targeting extracellular HMGB1 elicits a profound remodeling of tumor immune microenvironment for efficient cancer therapy. Indeed, without affecting the global number of (CD45+) immune cells, drastic reductions of monocytic/granulocytic myeloid-derived suppressor cells (MDSC) and regulatory T lymphocytes, a higher M1/M2 ratio of macrophages as well as an increased activation of both DC and pDC were continually observed following HMGB1 inhibition. Moreover, blocking HMGB1 improved the efficacy of anti-PD-1 cancer monoimmunotherapy. We also reported that a significant fraction of HMGB1 encountered within cancer microenvironment (interstitial fluids) is oxidized and, in opposite to its reduced isoform, oxidized HMGB1 acts as a tolerogenic signal in a receptor for advanced glycation endproducts-dependent manner.ConclusionCollectively, we present evidence that extracellular HMGB1 blockade may complement first-generation cancer immunotherapies by remobilizing antitumor immune response.