Cancer metabolism: current perspectives and future directions

Cellular metabolism influences life and death decisions. An emerging theme in cancer biology is that metabolic regulation is intricately linked to cancer progression. In part, this is due to the fact that proliferation is tightly regulated by availability of nutrients. Mitogenic signals promote nutrient uptake and synthesis of DNA, RNA, proteins and lipids. Therefore, it seems straight-forward that oncogenes, that often promote proliferation, also promote metabolic changes. In this review we summarize our current understanding of how ‘metabolic transformation' is linked to oncogenic transformation, and why inhibition of metabolism may prove a cancer′s ‘Achilles' heel'. On one hand, mutation of metabolic enzymes and metabolic stress sensors confers synthetic lethality with inhibitors of metabolism. On the other hand, hyperactivation of oncogenic pathways makes tumors more susceptible to metabolic inhibition. Conversely, an adequate nutrient supply and active metabolism regulates Bcl-2 family proteins and inhibits susceptibility to apoptosis. Here, we provide an overview of the metabolic pathways that represent anti-cancer targets and the cell death pathways engaged by metabolic inhibitors. Additionally, we will detail the similarities between metabolism of cancer cells and metabolism of proliferating cells

The Mnn2 Mannosyltransferase Family Modulates Mannoprotein Fibril Length, Immune Recognition and Virulence of Candida albicans

The fungal cell wall is the first point of interaction between an invading fungal pathogen and the host immune system. The outer layer of the cell wall is comprised of GPI anchored proteins, which are post-translationally modified by both N- and O-linked glycans. These glycans are important pathogen associated molecular patterns (PAMPs) recognised by the innate immune system. Glycan synthesis is mediated by a series of glycosyl transferases, located in the endoplasmic reticulum and Golgi apparatus. Mnn2 is responsible for the addition of the initial α1,2-mannose residue onto the α1,6-mannose backbone, forming the N-mannan outer chain branches. In Candida albicans, the MNN2 gene family is comprised of six members (MNN2, MNN21, MNN22, MNN23, MNN24 and MNN26). Using a series of single, double, triple, quintuple and sextuple mutants, we show, for the first time, that addition of α1,2-mannose is required for stabilisation of the α1,6-mannose backbone and hence regulates mannan fibril length. Sequential deletion of members of the MNN2 gene family resulted in the synthesis of lower molecular weight, less complex and more uniform N-glycans, with the sextuple mutant displaying only un-substituted α1,6-mannose. TEM images confirmed that the sextuple mutant was completely devoid of the outer mannan fibril layer, while deletion of two MNN2 orthologues resulted in short mannan fibrils. These changes in cell wall architecture correlated with decreased proinflammatory cytokine induction from monocytes and a decrease in fungal virulence in two animal models. Therefore, α1,2-mannose of N-mannan is important for both immune recognition and virulence of C. albicans

Author Correction:Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis

We thank the BBSRC, SULSA BioSKAPE and Pfizer Inc. for funding for a studentship for F.M.R. and the Wellcome Trust (086827, 075470, 099215, 099197 and 101873) and a Wellcome Trust ISSF award (105625), MRC CiC (MC_PC_14114) and MRC Centre for Medical Mycology and University of Aberdeen for funding and a Wellcome Trust Strategic Award (097377) and a Wellcome Trust grant 099197MA to T.F. and FCT Investigator IF/00033/2012 and PTDC/QUI-QUI/112537/2009 to A.S.P. We thank Ian Broadbent, Angus McDonald and Ron Gladue for constructive discussions; Chris Boston and Amanda Fitzgerald for advice on antibody expression and purification; Ed Lavallie and Wayne Stochaj for design and expression of the recombinant Hyr1; Louise Walker for high-pressure freezing of samples for TEM analysis; Jeanette Wagener for endotoxin testing of mAbs for in vivo experiments; Yan Liu of the Glycosciences laboratory for insight in the analysis with N-glycan array; Rebecca Hall and Mark Gresnigt for providing fungal strains; Andrew Limper and Theodore J. Kottom for providing Pneumocystis infected lung tissue extracts; David Williams for C. albicans mannoprotein; Christopher Thornton for A. fumigatus mannoprotein; Katie J. Doores for mAb PGT 128; and Gordon Brown for the murine Fc-Dectin-1. We are grateful to Lucinda Wight, Debbie Wilkinson and Kevin MacKenzie in the Microscopy and Histology Core Facility (Aberdeen University) and Raif Yuecel in the Iain Fraser Cytometry Centre (Aberdeen University) for their expert help with microscopy and cytometry experiments. We are also grateful to the staff at the University of Aberdeen Medical Research Facility for assistance with in vivo experiments and members of the Glycosciences Laboratory for their support of the Carbohydrate Microarray Facility. 18 January 2019 - Author Correction: Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis F. M. Rudkin, I. Raziunaite, H. Workman, S. Essono, R. Belmonte, D. M. MacCallum, E. M. Johnson, L. Silva, A. S. Palma, T. Feizi, A. Jensen, L. P. Erwig & N. A. R. Gow Nature Communicationsvolume 10, Article number: 394 (2019)Peer reviewedPublisher PD

Priorities for synthesis research in ecology and environmental science

Synthesis research in ecology and environmental science improves understanding, advances theory, identifies research priorities, and supports management strategies by linking data, ideas, and tools. Accelerating environmental challenges increases the need to focus synthesis science on the most pressing questions. To leverage input from the broader research community, we convened a virtual workshop with participants from many countries and disciplines to examine how and where synthesis can address key questions and themes in ecology and environmental science in the coming decade. Seven priority research topics emerged: (1) diversity, equity, inclusion, and justice (DEIJ), (2) human and natural systems, (3) actionable and use-inspired science, (4) scale, (5) generality, (6) complexity and resilience, and (7) predictability. Additionally, two issues regarding the general practice of synthesis emerged: the need for increased participant diversity and inclusive research practices; and increased and improved data flow, access, and skill-building. These topics and practices provide a strategic vision for future synthesis in ecology and environmental science

Differential high-affinity interaction of dectin-1 with natural or synthetic glucans is dependent upon primary structure and is influenced by polymer chain length and side-chain branching.

Glucans are structurally diverse fungal biopolymers that stimulate innate immunity and are fungal pathogen-associated molecular patterns. Dectin-1 is a C-type lectin-like pattern recognition receptor that binds glucans and induces innate immune responses to fungal pathogens. We examined the effect of glucan structure on recognition and binding by murine recombinant Dectin-1 with a library of natural product and synthetic (1-->3)-beta/(1-->6)-beta-glucans as well as nonglucan polymers. Dectin-1 is highly specific for glucans with a pure (1-->3)-beta-linked backbone structure. Although Dectin-1 is highly specific for (1-->3)-beta-d-glucans, it does not recognize all glucans equally. Dectin-1 differentially interacted with (1-->3)-beta-d-glucans over a very wide range of binding affinities (2.6 mM-2.2 pM). One of the most striking observations that emerged from this study was the remarkable high-affinity interaction of Dectin-1 with certain glucans (2.2 pM). These data also demonstrated that synthetic glucan ligands interact with Dectin-1 and that binding affinity increased in synthetic glucans containing a single glucose side-chain branch. We also observed differential recognition of glucans derived from saprophytes and pathogens. We found that glucan derived from a saprophytic yeast was recognized with higher affinity than glucan derived from the pathogen Candida albicans. Structural analysis demonstrated that glucan backbone chain length and (1-->6)-beta side-chain branching strongly influenced Dectin-1 binding affinity. These data demonstrate: 1) the specificity of Dectin-1 for glucans; 2) that Dectin-1 differentiates between glucan ligands based on structural determinants; and 3) that Dectin-1 can recognize and interact with both natural product and synthetic glucan ligands