Is still there a place for orteronel in management of prostate cancer?: Data from a literature based meta-analysis of randomized trials

Publication date: Available online 28 February 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Giandomenico Roviello, Chiara Pacifico, Giorgio Chiriacò, Daniele Generali
Orteronel (TAK-700) is an oral, non-steroidal 17,20-lyase inhibitor with higher specificity for 17,20 lyase over 17 hydroxylase. The first phase III studies showed an advantage with orteronel compared with placebo in terms of progression free survival and response of PSA. Unfortunately orteronel did not significantly prolong the overall survival. In order to assess the efficacy of orteronel in prostate cancer, we evaluated all available data on orteronel in the management of prostate cancer. A total of 2716 patients were evaluated from 3 randomized trials. We showed orteronel improved the progression free survival, time to PSA progression and PSA response compared with the placebo. In conclusion, given the limitations a literature rather than on individual patients' data meta-analysis, our data show a clinical efficacy of orteronel in prostate cancer, therefore we deem that orteronel may be investigated in combination with the other approved agents for CRPC or be tested in prior setting of disease such as the hormone sensitive prostate cancer.



http://ift.tt/2mIeTXl

β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Emily L. Goldberg, Jennifer L. Asher, Ryan D. Molony, Albert C. Shaw, Caroline J. Zeiss, Chao Wang, Ludmilla A. Morozova-Roche, Raimund I. Herzog, Akiko Iwasaki, Vishwa Deep Dixit
Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1β (IL-1β) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.

Graphical abstract

Teaser

NLRP3 inflammasome activation in macrophages and neutrophils drives painful inflammation during gout. Goldberg et al. report that ketogenic diet prevents systemic inflammation and joint damage in a rat model of gouty flare. Mechanistically, the ketone body β-hydroxybutyrate, the most abundant ketone in vivo, inhibits NLRP3/caspase-1-dependent IL-1β secretion from neutrophils.


http://ift.tt/2lm1dQQ

Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Hongqi Liu, Xizhi Feng, Kelli N. Ennis, Catherine A. Behrmann, Pranjal Sarma, Tony T. Jiang, Satoshi Kofuji, Liang Niu, Yiwen Stratton, Hala Elnakat Thomas, Sang-Oh Yoon, Atsuo T. Sasaki, David R. Plas
Genetic S6K1 inactivation can induce apoptosis in PTEN-deficient cells. We analyzed the therapeutic potential of S6K1 inhibitors in PTEN-deficient T cell leukemia and glioblastoma. Results revealed that the S6K1 inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively in PTEN-deficient cells. In vivo, AD80 rescued 50% of mice transplanted with PTEN-deficient leukemia cells. Cells surviving LY-2779964 treatment exhibited inhibitor-induced S6K1 phosphorylation due to increased mTOR-S6K1 co-association, which primed the rapid recovery of S6K1 signaling. In contrast, AD80 avoided S6K1 phosphorylation and mTOR co-association, resulting in durable suppression of S6K1-induced signaling and protein synthesis. Kinome analysis revealed that AD80 coordinately inhibits S6K1 together with the TAM family tyrosine kinase AXL. TAM suppression by BMS-777607 or genetic knockdown potentiated cytotoxic responses to LY-2779964 in PTEN-deficient glioblastoma cells. These results reveal that combination targeting of S6K1 and TAMs is a potential strategy for treatment of PTEN-deficient malignancy.

Graphical abstract

Teaser

Liu et al. find that the S6K1 inhibitor, AD80, is selectively cytotoxic for PTEN-deficient cancer cells, while LY-2779964 is ineffective as a single agent. AD80 avoids S6K1 priming and co-targets TAM tyrosine kinases. Combining LY-2779964 with the TAM kinase inhibitor BMS-777607 is selectively cytotoxic for PTEN-deficient cells.


http://ift.tt/2lm4ijT

Non-enzymatic N-acetylation of Lysine Residues by AcetylCoA Often Occurs via a Proximal S-acetylated Thiol Intermediate Sensitive to Glyoxalase II

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Andrew M. James, Kurt Hoogewijs, Angela Logan, Andrew R. Hall, Shujing Ding, Ian M. Fearnley, Michael P. Murphy
Acetyl coenzyme A (AcCoA), a key intermediate in mitochondrial metabolism, N-acetylates lysine residues, disrupting and, in some cases, regulating protein function. The mitochondrial lysine deacetylase Sirtuin 3 (Sirt3) reverses this modification with benefits reported in diabetes, obesity, and aging. We show that non-enzymatic lysine N-acetylation by AcCoA is greatly enhanced by initial acetylation of a cysteine residue, followed by SN-transfer of the acetyl moiety to a nearby lysine on mitochondrial proteins and synthetic peptides. The frequent occurrence of an S-acetyl intermediate before lysine N-acetylation suggests that proximity to a thioester is a key determinant of lysine susceptibility to acetylation. The thioesterase glyoxalase II (Glo2) can limit protein S-acetylation, thereby preventing subsequent lysine N-acetylation. This suggests that the hitherto obscure role of Glo2 in mitochondria is to act upstream of Sirt3 in minimizing protein N-acetylation, thus limiting protein dysfunction when AcCoA accumulates.

Graphical abstract

Teaser

James et al. show that the non-enzymatic N-acetylation of lysine residues in mitochondrial proteins frequently occurs via a proximal S-acetylated thiol intermediate. Glutathione equilibrates with this intermediate, allowing the thioesterase glyoxalase II to limit protein lysine N-acetylation. These findings expand our understanding of how protein acetylation arises.


http://ift.tt/2lmbHj2

Actin/Myosin-V- and Activity-Dependent Inter-synaptic Vesicle Exchange in Central Neurons

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Michael W. Gramlich, Vitaly A. Klyachko
Vesicle sharing between synaptic boutons is an important component of the recycling process that synapses employ to maintain vesicle pools. However, the mechanisms supporting and regulating vesicle transport during the inter-synaptic exchange remain poorly understood. Using nanometer-resolution tracking of individual synaptic vesicles and advanced computational algorithms, we find that long-distance axonal transport of synaptic vesicles between hippocampal boutons is partially mediated by the actin network, with myosin V as the primary actin-dependent motor that drives this vesicle transport. Furthermore, we find that vesicle exit from the synapse to the axon and long-distance vesicle transport are both rapidly and dynamically regulated by activity. We corroborated these findings with two complementary modeling approaches of vesicle exit, which closely reproduced experimental observations. These findings uncover the roles of actin and myosin V in supporting the inter-synaptic vesicle exchange and reveal that this process is dynamically modulated in an activity-dependent manner.

Graphical abstract

Teaser

Gramlich and Klyachko uncover the roles of actin and myosin V in supporting vesicle transport during inter-synaptic exchange (ISVE). They also reveal that this process is rapidly and dynamically modulated in an activity-dependent manner.


http://ift.tt/2lm8sby

Ultrastructural Characterization of Zika Virus Replication Factories

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Mirko Cortese, Sarah Goellner, Eliana Gisela Acosta, Christopher John Neufeldt, Olga Oleksiuk, Marko Lampe, Uta Haselmann, Charlotta Funaya, Nicole Schieber, Paolo Ronchi, Martin Schorb, Priit Pruunsild, Yannick Schwab, Laurent Chatel-Chaix, Alessia Ruggieri, Ralf Bartenschlager
A global concern has emerged with the pandemic spread of Zika virus (ZIKV) infections that can cause severe neurological symptoms in adults and newborns. ZIKV is a positive-strand RNA virus replicating in virus-induced membranous replication factories (RFs). Here we used various imaging techniques to investigate the ultrastructural details of ZIKV RFs and their relationship with host cell organelles. Analyses of human hepatic cells and neural progenitor cells infected with ZIKV revealed endoplasmic reticulum (ER) membrane invaginations containing pore-like openings toward the cytosol, reminiscent to RFs in Dengue virus-infected cells. Both the MR766 African strain and the H/PF/2013 Asian strain, the latter linked to neurological diseases, induce RFs of similar architecture. Importantly, ZIKV infection causes a drastic reorganization of microtubules and intermediate filaments forming cage-like structures surrounding the viral RF. Consistently, ZIKV replication is suppressed by cytoskeleton-targeting drugs. Thus, ZIKV RFs are tightly linked to rearrangements of the host cell cytoskeleton.

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Teaser

Cortese et al. show that ZIKV infection in both human hepatoma and neuronal progenitor cells induces drastic structural modification of the cellular architecture. Microtubules and intermediate filaments surround the viral replication factory composed of vesicles corresponding to ER membrane invagination toward the ER lumen. Importantly, alteration of microtubule flexibility impairs ZIKV replication.


http://ift.tt/2lm4gbL

Deciphering Subunit-Specific Functions within SWI/SNF Complexes

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Amanda L. Hughes, Tom Owen-Hughes
In this issue of Cell Reports, Sen et al. and Dutta et al. reveal the modularity of the yeast SWI/SNF chromatin remodeling complex and show that loss of different subunits leads to distinct consequences for gene expression.

Teaser

In this issue of Cell Reports, Sen et al. and Dutta et al. reveal the modularity of the yeast SWI/SNF chromatin remodeling complex and show that loss of different subunits leads to distinct consequences for gene expression.


http://ift.tt/2lme8Cj

Composition and Function of Mutant Swi/Snf Complexes

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Arnob Dutta, Mihaela Sardiu, Madelaine Gogol, Joshua Gilmore, Daoyong Zhang, Laurence Florens, Susan M. Abmayr, Michael P. Washburn, Jerry L. Workman
The 12-subunit Swi/Snf chromatin remodeling complex is conserved from yeast to humans. It functions to alter nucleosome positions by either sliding nucleosomes on DNA or evicting histones. Interestingly, 20% of all human cancers carry mutations in subunits of the Swi/Snf complex. Many of these mutations cause protein instability and loss, resulting in partial Swi/Snf complexes. Although several studies have shown that histone acetylation and activator-dependent recruitment of Swi/Snf regulate its function, it is less well understood how subunits regulate stability and function of the complex. Using functional proteomic and genomic approaches, we have assembled the network architecture of yeast Swi/Snf. In addition, we find that subunits of the Swi/Snf complex regulate occupancy of the catalytic subunit Snf2, thereby modulating gene transcription. Our findings have direct bearing on how cancer-causing mutations in orthologous subunits of human Swi/Snf may lead to aberrant regulation of gene expression by this complex.

Graphical abstract

Teaser

Subunits of the Swi/Snf chromatin-remodeling complex are mutated in 20% of cancers. Dutta et al. report modularity within yeast Swi/Snf that regulates both architecture and genomic functions of the complex. These findings will help predict complex composition in diseased states where subunits of the complex are mutated.


http://ift.tt/2lQSCck

Loss of Snf5 Induces Formation of an Aberrant SWI/SNF Complex

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Payel Sen, Jie Luo, Arjan Hada, Solomon G. Hailu, Mekonnen Lemma Dechassa, Jim Persinger, Sandipan Brahma, Somnath Paul, Jeff Ranish, Blaine Bartholomew
The SWI/SNF chromatin remodeling complex is highly conserved from yeast to human, and aberrant SWI/SNF complexes contribute to human disease. The Snf5/SMARCB1/INI1 subunit of SWI/SNF is a tumor suppressor frequently lost in pediatric rhabdoid cancers. We examined the effects of Snf5 loss on the composition, nucleosome binding, recruitment, and remodeling activities of yeast SWI/SNF. The Snf5 subunit is shown by crosslinking-mass spectrometry (CX-MS) and subunit deletion analysis to interact with the ATPase domain of Snf2 and to form a submodule consisting of Snf5, Swp82, and Taf14. Snf5 promotes binding of the Snf2 ATPase domain to nucleosomal DNA and enhances the catalytic and nucleosome remodeling activities of SWI/SNF. Snf5 is also required for SWI/SNF recruitment by acidic transcription factors. RNA-seq analysis suggests that both the recruitment and remodeling functions of Snf5 are required in vivo for SWI/SNF regulation of gene expression. Thus, loss of SNF5 alters the structure and function of SWI/SNF.

Graphical abstract

Teaser

Mutation of SWI/SNF chromatin remodeling complex subunits contributes to cancer and neurological disorders. Sen et al. report that loss of the Snf5 subunit alters the architecture and function of SWI/SNF in a yeast model system. These findings may reflect changes that occur in pediatric rhabdoid tumors with mutated Snf5.


http://ift.tt/2lQXFcO

The SETD8/PR-Set7 Methyltransferase Functions as a Barrier to Prevent Senescence-Associated Metabolic Remodeling

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Hiroshi Tanaka, Shin-ichiro Takebayashi, Akihisa Sakamoto, Tomoka Igata, Yuko Nakatsu, Noriko Saitoh, Shinjiro Hino, Mitsuyoshi Nakao
Cellular senescence is an irreversible growth arrest that contributes to development, tumor suppression, and age-related conditions. Senescent cells show active metabolism compared with proliferating cells, but the underlying mechanisms remain unclear. Here we show that the SETD8/PR-Set7 methyltransferase, which catalyzes mono-methylation of histone H4 at lysine 20 (H4K20me1), suppresses nucleolar and mitochondrial activities to prevent cellular senescence. SETD8 protein was selectively downregulated in both oncogene-induced and replicative senescence. Inhibition of SETD8 alone was sufficient to trigger senescence. Under these states, the expression of genes encoding ribosomal proteins (RPs) and ribosomal RNAs as well as the cyclin-dependent kinase (CDK) inhibitor p16^INK4A was increased, with a corresponding reduction of H4K20me1 at each locus. As a result, the loss of SETD8 concurrently stimulated nucleolar function and retinoblastoma protein-mediated mitochondrial metabolism. In conclusion, our data demonstrate that SETD8 acts as a barrier to prevent cellular senescence through chromatin-mediated regulation of senescence-associated metabolic remodeling.

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Teaser

Tanaka et al. show that SETD8/PR-Set7 methyltransferase represses senescence-associated genes including ribosomal proteins, ribosomal RNAs, and p16^INK4A by catalyzing mono-methylation of histone H4 at lysine 20. Depletion of SETD8 derepresses these genes, resulting in nucleolar and mitochondrial coactivation characteristic of senescence-associated metabolic remodeling.


http://ift.tt/2lQXPku

BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Simon J. Hogg, Stephin J. Vervoort, Sumit Deswal, Christopher J. Ott, Jason Li, Leonie A. Cluse, Paul A. Beavis, Phillip K. Darcy, Benjamin P. Martin, Andrew Spencer, Anna K. Traunbauer, Irina Sadovnik, Karin Bauer, Peter Valent, James E. Bradner, Johannes Zuber, Jake Shortt, Ricky W. Johnstone
BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncover an interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provide mechanistic insight into the transcriptional regulation of CD274.

Graphical abstract

Teaser

Hogg et al. find that BET bromodomain inhibitors promote anti-tumor immune responses through transcriptional repression of immune checkpoint ligand PD-L1 in genetically diverse tumor models and in response to inflammatory stimuli. Moreover, BET inhibitors enhance the efficacy of immune modulating therapies, such as checkpoint blockade.


http://ift.tt/2lQXi1P

Vaccine Elicitation of High Mannose-Dependent Neutralizing Antibodies against the V3-Glycan Broadly Neutralizing Epitope in Nonhuman Primates

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Kevin O. Saunders, Nathan I. Nicely, Kevin Wiehe, Mattia Bonsignori, R. Ryan Meyerhoff, Robert Parks, William E. Walkowicz, Baptiste Aussedat, Nelson R. Wu, Fangping Cai, Yusuf Vohra, Peter K. Park, Amanda Eaton, Eden P. Go, Laura L. Sutherland, Richard M. Scearce, Dan H. Barouch, Ruijun Zhang, Tarra Von Holle, R. Glenn Overman, Kara Anasti, Rogier W. Sanders, M. Anthony Moody, Thomas B. Kepler, Bette Korber, Heather Desaire, Sampa Santra, Norman L. Letvin, Gary J. Nabel, David C. Montefiori, Georgia D. Tomaras, Hua-Xin Liao, S. Munir Alam, Samuel J. Danishefsky, Barton F. Haynes
Induction of broadly neutralizing antibodies (bnAbs) that target HIV-1 envelope (Env) is a goal of HIV-1 vaccine development. A bnAb target is the Env third variable loop (V3)-glycan site. To determine whether immunization could induce antibodies to the V3-glycan bnAb binding site, we repetitively immunized macaques over a 4-year period with an Env expressing V3-high mannose glycans. Env immunizations elicited plasma antibodies that neutralized HIV-1 expressing only high-mannose glycans—a characteristic shared by early bnAb B cell lineage members. A rhesus recombinant monoclonal antibody from a vaccinated macaque bound to the V3-glycan site at the same amino acids as broadly neutralizing antibodies. A structure of the antibody bound to glycan revealed that the three variable heavy-chain complementarity-determining regions formed a cavity into which glycan could insert and neutralized multiple HIV-1 isolates with high-mannose glycans. Thus, HIV-1 Env vaccination induced mannose-dependent antibodies with characteristics of V3-glycan bnAb precursors.

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Teaser

Most bnAb epitopes on HIV-1 Envelope include host glycans, but previous Env vaccines have not induced glycan-dependent antibodies. Saunders et al. describe here the ontogeny, crystal structure with glycan, and virion Man9GlcNAc2-dependent neutralization for glycan-reactive antibodies induced by envelope vaccination.


http://ift.tt/2lR2til

BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Cristian R. Smulski, Patrick Kury, Lea M. Seidel, Hannah S. Staiger, Anna K. Edinger, Laure Willen, Maximilan Seidl, Henry Hess, Ulrich Salzer, Antonius G. Rolink, Marta Rizzi, Pascal Schneider, Hermann Eibel
B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing. Inhibition of ADAM10 augments BAFF-dependent survival of primary human B cells, whereas inhibition of ADAM17 increases BAFFR expression levels on germinal center B cells. Therefore, BAFF-induced processing of BAFFR regulates BAFF-mediated B cell responses in a TACI-dependent manner.

Graphical abstract

Teaser

Smulski et al. report that the B cell survival receptor BAFFR undergoes ligand-induced shedding but only in cells co-expressing a second receptor for BAFF called TACI. BAFFR shedding can be performed by ADAM10 in circulating B cells or by ADAM17 in germinal center B cells and limits BAFF-mediated survival signals.


http://ift.tt/2lQXoH5

Coordinated Movement of Vesicles and Actin Bundles during Nerve Growth Revealed by Superresolution Microscopy

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Motohiro Nozumi, Fubito Nakatsu, Kaoru Katoh, Michihiro Igarashi
The growth cone is an essential structure for nerve growth. Although its membrane and cytoskeleton are likely to interact coordinately during nerve growth, the mechanisms are unknown due to their close proximity. Here, we used superresolution microscopy to simultaneously observe vesicles and F-actin in growth cones. We identified a novel vesicular generation mechanism that is independent of clathrin and dependent on endophilin-3- and dynamin-1 and that occurs proximal to the leading edge simultaneously with fascin-1-dependent F-actin bundling. In contrast to conventional clathrin-dependent endocytosis, which occurs distal from the leading edge at the basal surfaces of growth cones, this mechanism was distinctly observed at the apical surface using 3D imaging and was involved in mediating axon growth. Reduced endophilin or fascin inhibited this endocytic mechanism. These results suggest that, at the leading edge, vesicles are coordinately generated and transported with actin bundling during nerve growth.

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Teaser

Nozumi et al. simultaneously observe the movements of vesicles and F-actin in growth cones using SIM superresolution microscopy to characterize their coordinated trafficking at the leading edge. They find that endophilin-mediated endocytosis is linked to fascin-dependent F-actin bundling during nerve growth, while clathrin-mediated endocytosis is not.


http://ift.tt/2lR39nZ

Varying Intolerance of Gene Pathways to Mutational Classes Explain Genetic Convergence across Neuropsychiatric Disorders

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Shahar Shohat, Eyal Ben-David, Sagiv Shifman
Genetic susceptibility to intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ) often arises from mutations in the same genes, suggesting that they share common mechanisms. We studied genes with de novo mutations in the three disorders and genes implicated in SCZ by genome-wide association study (GWAS). Using biological annotations and brain gene expression, we show that mutation class explains enrichment patterns more than specific disorder. Genes with loss-of-function mutations and genes with missense mutations were associated with different pathways across disorders. Conversely, gene expression patterns were specific for each disorder. ID genes were preferentially expressed in the cortex; ASD genes were expressed in the fetal cortex, cerebellum, and striatum; and genes associated with SCZ were expressed in the adolescent cortex. Our study suggests that convergence across neuropsychiatric disorders stems from common pathways that are consistently vulnerable to genetic variations but that spatiotemporal activity of genes contributes to specific phenotypes.

Graphical abstract

Teaser

Shahar et al. performed a systematic comparison of genes implicated in intellectual disability, autism spectrum disorder, and schizophrenia. Using systems biology tools, they show that mutation class explains enrichment patterns more than specific disorder. In contrast, they find unique patterns of brain expression for genes associated with each disorder.


http://ift.tt/2lQRfuh

Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Ayano Kondo, Shogo Yamamoto, Ryo Nakaki, Teppei Shimamura, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Tetsuo Yoshida, Hiroyuki Aburatani, Tsuyoshi Osawa
Conditions of the tumor microenvironment, such as hypoxia and nutrient starvation, play critical roles in cancer progression. However, the role of acidic extracellular pH in cancer progression is not studied as extensively as that of hypoxia. Here, we show that extracellular acidic pH (pH 6.8) triggered activation of sterol regulatory element-binding protein 2 (SREBP2) by stimulating nuclear translocation and promoter binding to its targets, along with intracellular acidification. Interestingly, inhibition of SREBP2, but not SREBP1, suppressed the upregulation of low pH-induced cholesterol biosynthesis-related genes. Moreover, acyl-CoA synthetase short-chain family member 2 (ACSS2), a direct SREBP2 target, provided a growth advantage to cancer cells under acidic pH. Furthermore, acidic pH-responsive SREBP2 target genes were associated with reduced overall survival of cancer patients. Thus, our findings show that SREBP2 is a key transcriptional regulator of metabolic genes and progression of cancer cells, partly in response to extracellular acidification.

Graphical abstract

Teaser

Kondo et al. find that extracellular acidic pH induces different cellular responses than hypoxia and nutrient starvation. SREBP2 is a key transcriptional regulator of cholesterol biosynthetic genes and ACSS2 in response to extracellular acidification. SREBP2 target genes increase tumor growth in low pH and correlate with decreased survival in patients.


http://ift.tt/2lQXMFk

Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the Absence of Oncogenic Drivers

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Nirakar Rajbhandari, Wan-chi Lin, Barbara L. Wehde, Aleata A. Triplett, Kay-Uwe Wagner
Mutant KRAS and c-MYC are oncogenic drivers and rational therapeutic targets for the treatment of pancreatic cancer. Although tumor growth and homeostasis are largely dependent on these oncogenes, a few residual cancer cells are able to survive the ablation of mutant KRAS and c-MYC. By performing a genome-wide gene expression analysis of in vivo-derived bulk tumor cells and residual cancer cells lacking the expression of mutant KRAS or c-MYC, we have identified an increase in autocrine IGF1/AKT signaling as a common survival mechanism in dormant cancer cells. The pharmacological inhibition of IGF-1R reduces residual disease burden and cancer recurrence, suggesting that this molecular pathway is crucial for the survival of cancer cells in the absence of the primary oncogenic drivers.

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Teaser

Rajbhandari et al. demonstrate that an increase in autocrine IGF1 signaling mediates the survival of residual pancreatic cancer cells following the ablation of oncogenic drivers (mutant KRAS and c-MYC). They provide experimental evidence that inhibiting IGF-1R can eradicate minimal residual disease and reduce cancer recurrence in vivo.


http://ift.tt/2lQTjCo

miR-600 Acts as a Bimodal Switch that Regulates Breast Cancer Stem Cell Fate through WNT Signaling

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Rita El Helou, Guillaume Pinna, Olivier Cabaud, Julien Wicinski, Ricky Bhajun, Laurent Guyon, Claire Rioualen, Pascal Finetti, Abigaelle Gros, Bernard Mari, Pascal Barbry, Francois Bertucci, Ghislain Bidaut, Annick Harel-Bellan, Daniel Birnbaum, Emmanuelle Charafe-Jauffret, Christophe Ginestier
Breast cancer stem cells (bCSCs) have been implicated in tumor progression and therapeutic resistance; however, the molecular mechanisms that define this state are unclear. We have performed two microRNA (miRNA) gain- and loss-of-function screens to identify miRNAs that regulate the choice between bCSC self-renewal and differentiation. We find that micro-RNA (miR)-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal, leading to decreased in vivo tumorigenicity. miR-600 targets stearoyl desaturase 1 (SCD1), an enzyme required to produce active, lipid-modified WNT proteins. In the absence of miR-600, WNT signaling is active and promotes self-renewal, whereas overexpression of miR-600 inhibits the production of active WNT and promotes bCSC differentiation. In a series of 120 breast tumors, we found that a low level of miR-600 is correlated with active WNT signaling and a poor prognosis. These findings highlight a miR-600-centered signaling network that governs bCSC-fate decisions and influences tumor progression.

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Teaser

El Helou et al. identify miRNAs that are able to balance bCSC fate. They find that miR-600 silencing results in bCSC expansion, while its overexpression reduces bCSC self-renewal. miR-600 was further found to regulate WNT signaling through SCD1, and miR-600 expression correlates with clinical outcome.


http://ift.tt/2lQRfdL

Plasma Dihydroceramides Are Diabetes Susceptibility Biomarker Candidates in Mice and Humans

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Leonore Wigger, Céline Cruciani-Guglielmacci, Anthony Nicolas, Jessica Denom, Neïké Fernandez, Frédéric Fumeron, Pedro Marques-Vidal, Alain Ktorza, Werner Kramer, Anke Schulte, Hervé Le Stunff, Robin Liechti, Ioannis Xenarios, Peter Vollenweider, Gérard Waeber, Ingo Uphues, Ronan Roussel, Christophe Magnan, Mark Ibberson, Bernard Thorens
Plasma metabolite concentrations reflect the activity of tissue metabolic pathways and their quantitative determination may be informative about pathogenic conditions. We searched for plasma lipid species whose concentrations correlate with various parameters of glucose homeostasis and susceptibility to type 2 diabetes (T2D). Shotgun lipidomic analysis of the plasma of mice from different genetic backgrounds, which develop a pre-diabetic state at different rates when metabolically stressed, led to the identification of a group of sphingolipids correlated with glucose tolerance and insulin secretion. Quantitative analysis of these and closely related lipids in the plasma of individuals from two population-based prospective cohorts revealed that specific long-chain fatty-acid-containing dihydroceramides were significantly elevated in the plasma of individuals who will progress to diabetes up to 9 years before disease onset. These lipids may serve as early biomarkers of, and help identify, metabolic deregulation in the pathogenesis of T2D.

Graphical abstract

Teaser

Wigger et al. find that several sphingolipids in mouse plasma correlate with glucose tolerance and insulin secretion. Quantitative analysis of these and closely related lipids in human plasma from two cohorts reveal that dihydroceramides are significantly elevated in individuals progressing to diabetes, up to 9 years before disease onset.


http://ift.tt/2lQRdm9

cis-Acting Complex-Trait-Associated lincRNA Expression Correlates with Modulation of Chromosomal Architecture

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): Jennifer Yihong Tan, Adam Alexander Thil Smith, Maria Ferreira da Silva, Cyril Matthey-Doret, Rico Rueedi, Reyhan Sönmez, David Ding, Zoltán Kutalik, Sven Bergmann, Ana Claudia Marques
Intergenic long noncoding RNAs (lincRNAs) are the largest class of transcripts in the human genome. Although many have recently been linked to complex human traits, the underlying mechanisms for most of these transcripts remain undetermined. We investigated the regulatory roles of a high-confidence and reproducible set of 69 trait-relevant lincRNAs (TR-lincRNAs) in human lymphoblastoid cells whose biological relevance is supported by their evolutionary conservation during recent human history and genetic interactions with other trait-associated loci. Their enrichment in enhancer-like chromatin signatures, interactions with nearby trait-relevant protein-coding loci, and preferential location at topologically associated domain (TAD) boundaries provide evidence that TR-lincRNAs likely regulate proximal trait-relevant gene expression in cis by modulating local chromosomal architecture. This is consistent with the positive and significant correlation found between TR-lincRNA abundance and intra-TAD DNA-DNA contacts. Our results provide insights into the molecular mode of action by which TR-lincRNAs contribute to complex human traits.

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Teaser

Tan et al. identify and characterize 69 human complex trait/disease-associated lincRNAs in LCLs. They show that these loci are often associated with cis-regulation of gene expression and tend to be localized at TAD boundaries, suggesting that these lincRNAs may influence chromosomal architecture.


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