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Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [918 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3175 journals]
  • Analysis of Human Sequence Data Reveals Two Pulses of Archaic Denisovan
           Admixture
    • Authors: Sharon R. Browning; Brian L. Browning; Ying Zhou; Serena Tucci; Joshua M. Akey
      Pages: 53 - 61.e9
      Abstract: Publication date: Available online 15 March 2018
      Source:Cell
      Author(s): Sharon R. Browning, Brian L. Browning, Ying Zhou, Serena Tucci, Joshua M. Akey
      Anatomically modern humans interbred with Neanderthals and with a related archaic population known as Denisovans. Genomes of several Neanderthals and one Denisovan have been sequenced, and these reference genomes have been used to detect introgressed genetic material in present-day human genomes. Segments of introgression also can be detected without use of reference genomes, and doing so can be advantageous for finding introgressed segments that are less closely related to the sequenced archaic genomes. We apply a new reference-free method for detecting archaic introgression to 5,639 whole-genome sequences from Eurasia and Oceania. We find Denisovan ancestry in populations from East and South Asia and Papuans. Denisovan ancestry comprises two components with differing similarity to the sequenced Altai Denisovan individual. This indicates that at least two distinct instances of Denisovan admixture into modern humans occurred, involving Denisovan populations that had different levels of relatedness to the sequenced Altai Denisovan. Video
      Graphical abstract image Teaser Two waves of Denisovan ancestry have shaped present-day humans.

      PubDate: 2018-03-19T11:28:30Z
      DOI: 10.1016/j.cell.2018.02.031
      Issue No: Vol. 173, No. 1 (2018)
       
  • Ribosome Levels Selectively Regulate Translation and Lineage Commitment in
           Human Hematopoiesis
    • Authors: Rajiv K. Khajuria; Mathias Munschauer; Jacob C. Ulirsch; Claudia Fiorini; Leif S. Ludwig; Sean K. McFarland; Nour J. Abdulhay; Harrison Specht; Hasmik Keshishian; D.R. Mani; Marko Jovanovic; Steven R. Ellis; Charles P. Fulco; Jesse M. Engreitz; Sabina Schütz; John Lian; Karen W. Gripp; Olga K. Weinberg; Geraldine S. Pinkus; Lee Gehrke; Aviv Regev; Eric S. Lander; Hanna T. Gazda; Winston Y. Lee; Vikram G. Panse; Steven A. Carr; Vijay G. Sankaran
      Pages: 90 - 103.e19
      Abstract: Publication date: Available online 15 March 2018
      Source:Cell
      Author(s): Rajiv K. Khajuria, Mathias Munschauer, Jacob C. Ulirsch, Claudia Fiorini, Leif S. Ludwig, Sean K. McFarland, Nour J. Abdulhay, Harrison Specht, Hasmik Keshishian, D.R. Mani, Marko Jovanovic, Steven R. Ellis, Charles P. Fulco, Jesse M. Engreitz, Sabina Schütz, John Lian, Karen W. Gripp, Olga K. Weinberg, Geraldine S. Pinkus, Lee Gehrke, Aviv Regev, Eric S. Lander, Hanna T. Gazda, Winston Y. Lee, Vikram G. Panse, Steven A. Carr, Vijay G. Sankaran
      Blood cell formation is classically thought to occur through a hierarchical differentiation process, although recent studies have shown that lineage commitment may occur earlier in hematopoietic stem and progenitor cells (HSPCs). The relevance to human blood diseases and the underlying regulation of these refined models remain poorly understood. By studying a genetic blood disorder, Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, we are able to gain mechanistic insight into how lineage commitment is programmed normally and disrupted in disease. We show that in DBA, the pool of available ribosomes is limited, while ribosome composition remains constant. Surprisingly, this global reduction in ribosome levels more profoundly alters translation of a select subset of transcripts. We show how the reduced translation of select transcripts in HSPCs can impair erythroid lineage commitment, illuminating a regulatory role for ribosome levels in cellular differentiation.
      Graphical abstract image Teaser A global reduction in ribosome levels in Diamond-Blackfan anemia profoundly alters translation of a select subset of transcripts, thereby impeding erythroid lineage commitment.

      PubDate: 2018-03-19T11:28:30Z
      DOI: 10.1016/j.cell.2018.02.036
      Issue No: Vol. 173, No. 1 (2018)
       
  • Tracking Cancer Evolution Reveals Constrained Routes to Metastases:
           TRACERx Renal
    • Abstract: Publication date: Available online 12 April 2018
      Source:Cell
      Author(s): Samra Turajlic, Hang Xu, Kevin Litchfield, Andrew Rowan, Tim Chambers, Jose I. Lopez, David Nicol, Tim O’Brien, James Larkin, Stuart Horswell, Mark Stares, Lewis Au, Mariam Jamal-Hanjani, Ben Challacombe, Ashish Chandra, Steve Hazell, Claudia Eichler-Jonsson, Aspasia Soultati, Simon Chowdhury, Sarah Rudman, Joanna Lynch, Archana Fernando, Gordon Stamp, Emma Nye, Faiz Jabbar, Lavinia Spain, Sharanpreet Lall, Rosa Guarch, Mary Falzon, Ian Proctor, Lisa Pickering, Martin Gore, Thomas B.K. Watkins, Sophia Ward, Aengus Stewart, Renzo DiNatale, Maria F. Becerra, Ed Reznik, James J. Hsieh, Todd A. Richmond, George F. Mayhew, Samantha M. Hill, Catherine D. McNally, Carol Jones, Heidi Rosenbaum, Stacey Stanislaw, Daniel L. Burgess, Nelson R. Alexander, Charles Swanton
      Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.
      Graphical abstract image Teaser A multi-center prospective study and two validation cohorts of matched primary metastasis biopsies from 100 patients with clear-cell renal cell carcinoma provides a comprehensive picture of the genetic underpinnings and the evolutionary patterns of metastasis.

      PubDate: 2018-04-16T09:09:49Z
       
  • In Silico Labeling: Predicting Fluorescent Labels in Unlabeled Images
    • Abstract: Publication date: Available online 12 April 2018
      Source:Cell
      Author(s): Eric M. Christiansen, Samuel J. Yang, D. Michael Ando, Ashkan Javaherian, Gaia Skibinski, Scott Lipnick, Elliot Mount, Alison O’Neil, Kevan Shah, Alicia K. Lee, Piyush Goyal, William Fedus, Ryan Poplin, Andre Esteva, Marc Berndl, Lee L. Rubin, Philip Nelson, Steven Finkbeiner
      Microscopy is a central method in life sciences. Many popular methods, such as antibody labeling, are used to add physical fluorescent labels to specific cellular constituents. However, these approaches have significant drawbacks, including inconsistency; limitations in the number of simultaneous labels because of spectral overlap; and necessary perturbations of the experiment, such as fixing the cells, to generate the measurement. Here, we show that a computational machine-learning approach, which we call “in silico labeling” (ISL), reliably predicts some fluorescent labels from transmitted-light images of unlabeled fixed or live biological samples. ISL predicts a range of labels, such as those for nuclei, cell type (e.g., neural), and cell state (e.g., cell death). Because prediction happens in silico, the method is consistent, is not limited by spectral overlap, and does not disturb the experiment. ISL generates biological measurements that would otherwise be problematic or impossible to acquire.
      Graphical abstract image Teaser In silico labeling, a machine-learning approach, reliably infers fluorescent measurements from transmitted-light images of unlabeled fixed or live biological samples.

      PubDate: 2018-04-16T09:09:49Z
       
  • Timing the Landmark Events in the Evolution of Clear Cell Renal Cell
           Cancer: TRACERx Renal
    • Abstract: Publication date: Available online 12 April 2018
      Source:Cell
      Author(s): Thomas J. Mitchell, Samra Turajlic, Andrew Rowan, David Nicol, James H.R. Farmery, Tim O’Brien, Inigo Martincorena, Patrick Tarpey, Nicos Angelopoulos, Lucy R. Yates, Adam P. Butler, Keiran Raine, Grant D. Stewart, Ben Challacombe, Archana Fernando, Jose I. Lopez, Steve Hazell, Ashish Chandra, Simon Chowdhury, Sarah Rudman, Aspasia Soultati, Gordon Stamp, Nicos Fotiadis, Lisa Pickering, Lewis Au, Lavinia Spain, Joanna Lynch, Mark Stares, Jon Teague, Francesco Maura, David C. Wedge, Stuart Horswell, Tim Chambers, Kevin Litchfield, Hang Xu, Aengus Stewart, Reza Elaidi, Stéphane Oudard, Nicholas McGranahan, Istvan Csabai, Martin Gore, P. Andrew Futreal, James Larkin, Andy G. Lynch, Zoltan Szallasi, Charles Swanton, Peter J. Campbell
      Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5′ UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor’s most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.
      Graphical abstract image Teaser Combination of whole-genome sequencing analysis and a multi-region sampling approach provides insights into the nature and timing of key oncogenic events in clear cell renal cell carcinoma, depicts the evolutionary trajectories of tumors in patients and highlights the opportunity for early intervention.

      PubDate: 2018-04-16T09:09:49Z
       
  • DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ
           and PARP Inhibitor Sensitivity
    • Abstract: Publication date: Available online 12 April 2018
      Source:Cell
      Author(s): Rajat Gupta, Kumar Somyajit, Takeo Narita, Elina Maskey, Andre Stanlie, Magdalena Kremer, Dimitris Typas, Michael Lammers, Niels Mailand, Andre Nussenzweig, Jiri Lukas, Chunaram Choudhary
      Repair of damaged DNA is essential for maintaining genome integrity and for preventing genome-instability-associated diseases, such as cancer. By combining proximity labeling with quantitative mass spectrometry, we generated high-resolution interaction neighborhood maps of the endogenously expressed DNA repair factors 53BP1, BRCA1, and MDC1. Our spatially resolved interaction maps reveal rich network intricacies, identify shared and bait-specific interaction modules, and implicate previously concealed regulators in this process. We identified a novel vertebrate-specific protein complex, shieldin, comprising REV7 plus three previously uncharacterized proteins, RINN1 (CTC-534A2.2), RINN2 (FAM35A), and RINN3 (C20ORF196). Recruitment of shieldin to DSBs, via the ATM-RNF8-RNF168-53BP1-RIF1 axis, promotes NHEJ-dependent repair of intrachromosomal breaks, immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres. Shieldin functions as a downstream effector of 53BP1-RIF1 in restraining DNA end resection and in sensitizing BRCA1-deficient cells to PARP inhibitors. These findings have implications for understanding cancer-associated PARPi resistance and the evolution of antibody CSR in higher vertebrates.
      Graphical abstract image Teaser Application of proximity-based quantitative proteomics allows the characterization of endogenous protein networks among major DNA damage repair factors and reveals the role of the protein complex shieldin in regulating NHEJ, antibody class switching, and sensitivity to PARP inhibitors.

      PubDate: 2018-04-16T09:09:49Z
       
  • Cancer-Germline Antigen Expression Discriminates Clinical Outcome to
           CTLA-4 Blockade
    • Abstract: Publication date: Available online 12 April 2018
      Source:Cell
      Author(s): Sachet A. Shukla, Pavan Bachireddy, Bastian Schilling, Christina Galonska, Qian Zhan, Clyde Bango, Rupert Langer, Patrick C. Lee, Daniel Gusenleitner, Derin B. Keskin, Mehrtash Babadi, Arman Mohammad, Andreas Gnirke, Kendell Clement, Zachary J. Cartun, Eliezer M. Van Allen, Diana Miao, Ying Huang, Alexandra Snyder, Taha Merghoub, Jedd D. Wolchok, Levi A. Garraway, Alexander Meissner, Jeffrey S. Weber, Nir Hacohen, Donna Neuberg, Patrick R. Potts, George F. Murphy, Christine G. Lian, Dirk Schadendorf, F. Stephen Hodi, Catherine J. Wu
      CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.
      Graphical abstract image Teaser Increased expression of a subcluster of MAGE-A cancer-germline antigens predicts resistance specific to CTLA-4, but not PD-1, blockade, and its association with autophagy suppression implicates the role of autophagy in regulating primary resistance to anti-CTLA-4 therapy in melanoma patients.

      PubDate: 2018-04-16T09:09:49Z
       
  • Deterministic Evolutionary Trajectories Influence Primary Tumor Growth:
           TRACERx Renal
    • Abstract: Publication date: Available online 12 April 2018
      Source:Cell
      Author(s): Samra Turajlic, Hang Xu, Kevin Litchfield, Andrew Rowan, Stuart Horswell, Tim Chambers, Tim O’Brien, Jose I. Lopez, Thomas B.K. Watkins, David Nicol, Mark Stares, Ben Challacombe, Steve Hazell, Ashish Chandra, Thomas J. Mitchell, Lewis Au, Claudia Eichler-Jonsson, Faiz Jabbar, Aspasia Soultati, Simon Chowdhury, Sarah Rudman, Joanna Lynch, Archana Fernando, Gordon Stamp, Emma Nye, Aengus Stewart, Wei Xing, Jonathan C. Smith, Mickael Escudero, Adam Huffman, Nik Matthews, Greg Elgar, Ben Phillimore, Marta Costa, Sharmin Begum, Sophia Ward, Max Salm, Stefan Boeing, Rosalie Fisher, Lavinia Spain, Carolina Navas, Eva Grönroos, Sebastijan Hobor, Sarkhara Sharma, Ismaeel Aurangzeb, Sharanpreet Lall, Alexander Polson, Mary Varia, Catherine Horsfield, Nicos Fotiadis, Lisa Pickering, Roland F. Schwarz, Bruno Silva, Javier Herrero, Nick M. Luscombe, Mariam Jamal-Hanjani, Rachel Rosenthal, Nicolai J. Birkbak, Gareth A. Wilson, Orsolya Pipek, Dezso Ribli, Marcin Krzystanek, Istvan Csabai, Zoltan Szallasi, Martin Gore, Nicholas McGranahan, Peter Van Loo, Peter Campbell, James Larkin, Charles Swanton
      The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.
      Graphical abstract image Teaser A multi-center prospective study on 101 patients with clear-cell renal cell carcinoma resolves the evolutionary features and subtypes underpinning the diverse clinical phenotypes of the disease and suggests these features as potential biomarkers for guiding intervention and surveillance.

      PubDate: 2018-04-16T09:09:49Z
       
  • Opposite Roles of Salicylic Acid Receptors NPR1 and NPR3/NPR4 in
           Transcriptional Regulation of Plant Immunity
    • Abstract: Publication date: Available online 12 April 2018
      Source:Cell
      Author(s): Yuli Ding, Tongjun Sun, Kevin Ao, Yujun Peng, Yaxi Zhang, Xin Li, Yuelin Zhang
      Salicylic acid (SA) is a plant defense hormone required for immunity. Arabidopsis NPR1 and NPR3/NPR4 were previously shown to bind SA and all three proteins were proposed as SA receptors. NPR1 functions as a transcriptional co-activator, whereas NPR3/NPR4 were suggested to function as E3 ligases that promote NPR1 degradation. Here we report that NPR3/NPR4 function as transcriptional co-repressors and SA inhibits their activities to promote the expression of downstream immune regulators. npr4-4D, a gain-of-function npr4 allele that renders NPR4 unable to bind SA, constitutively represses SA-induced immune responses. In contrast, the equivalent mutation in NPR1 abolishes its ability to bind SA and promote SA-induced defense gene expression. Further analysis revealed that NPR3/NPR4 and NPR1 function independently to regulate SA-induced immune responses. Our study indicates that both NPR1 and NPR3/NPR4 are bona fide SA receptors, but play opposite roles in transcriptional regulation of SA-induced defense gene expression.
      Graphical abstract image Teaser Salicylic acid receptors NPR1 and NPR3/NPR4 play opposite roles in the transcriptional regulation of plant defense against pathogens.

      PubDate: 2018-04-16T09:09:49Z
       
  • Charting a Course to a Cure
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Robert Kruger


      PubDate: 2018-04-11T14:59:47Z
       
  • Günter Blobel (1936–2018)
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Sanford M. Simon


      PubDate: 2018-04-11T14:59:47Z
       
  • The TCGA Legacy
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2


      PubDate: 2018-04-11T14:59:47Z
       
  • The Cancer Genome Atlas: Creating Lasting Value beyond Its Data
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Carolyn Hutter, Jean Claude Zenklusen
      The Cancer Genome Atlas (TCGA) team now presents the Pan-Cancer Atlas, investigating different aspects of cancer biology by analyzing the data generated during the 10+ years of the TCGA project.
      Teaser The Cancer Genome Atlas (TCGA) team now presents the Pan-Cancer Atlas, investigating different aspects of cancer biology by analyzing the data generated during the 10+ years of the TCGA project.

      PubDate: 2018-04-11T14:59:47Z
       
  • Pipped at the Post: Pipecolic Acid Derivative Identified as SAR Regulator
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Libo Shan, Ping He
      The non-protein amino acid pipecolic acid (Pip) is a lysine catabolite involved in plant systemic acquired resistance (SAR). In this issue of Cell, Hartmann et al. (2018) demonstrate that a flavin-dependent monooxygenase converts Pip to N-hydroxypipecolic acid (NHP), which functions as a critical metabolic regulator of SAR in Arabidopsis.
      Teaser The non-protein amino acid pipecolic acid (Pip) is a lysine catabolite involved in plant systemic acquired resistance (SAR). In this issue of Cell, Hartmann et al. (2018) demonstrate that a flavin-dependent monooxygenase converts Pip to N-hydroxypipecolic acid (NHP), which functions as a critical metabolic regulator of SAR in Arabidopsis.

      PubDate: 2018-04-11T14:59:47Z
       
  • Coupling Neurogenesis to Circuit Formation
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Ki-Jun Yoon, Guo-li Ming, Hongjun Song
      A central question in neuroscience is how developmental programs instruct the formation of complex neural circuits with temporal, spatial, and numerical precision. Pinto-Teixeira et al. (2018) reveal simple developmental rules that govern sequential neurogenesis to concurrently establish highly organized retinotopic maps in the Drosophila visual system.
      Teaser A central question in neuroscience is how developmental programs instruct the formation of complex neural circuits with temporal, spatial, and numerical precision. Pinto-Teixeira et al. (2018) reveal simple developmental rules that govern sequential neurogenesis to concurrently establish highly organized retinotopic maps in the Drosophila visual system.

      PubDate: 2018-04-11T14:59:47Z
       
  • Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000
           Tumors from 33 Types of Cancer
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Katherine A. Hoadley, Christina Yau, Toshinori Hinoue, Denise M. Wolf, Alexander J. Lazar, Esther Drill, Ronglai Shen, Alison M. Taylor, Andrew D. Cherniack, Vésteinn Thorsson, Rehan Akbani, Reanne Bowlby, Christopher K. Wong, Maciej Wiznerowicz, Francisco Sanchez-Vega, A. Gordon Robertson, Barbara G. Schneider, Michael S. Lawrence, Houtan Noushmehr, Tathiane M. Malta, Joshua M. Stuart, Christopher C. Benz, Peter W. Laird
      We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.
      Graphical abstract image Teaser Comprehensive, integrated molecular analysis identifies molecular relationships across a large diverse set of human cancers, suggesting future directions for exploring clinical actionability in cancer treatment.

      PubDate: 2018-04-11T14:59:47Z
       
  • Perspective on Oncogenic Processes at the End of the Beginning of Cancer
           Genomics
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Li Ding, Matthew H. Bailey, Eduard Porta-Pardo, Vesteinn Thorsson, Antonio Colaprico, Denis Bertrand, David L. Gibbs, Amila Weerasinghe, Kuan-lin Huang, Collin Tokheim, Isidro Cortés-Ciriano, Reyka Jayasinghe, Feng Chen, Lihua Yu, Sam Sun, Catharina Olsen, Jaegil Kim, Alison M. Taylor, Andrew D. Cherniack, Rehan Akbani, Chayaporn Suphavilai, Niranjan Nagarajan, Joshua M. Stuart, Gordon B. Mills, Matthew A. Wyczalkowski, Benjamin G. Vincent, Carolyn M. Hutter, Jean Claude Zenklusen, Katherine A. Hoadley, Michael C. Wendl, llya Shmulevich, Alexander J. Lazar, David A. Wheeler, Gad Getz
      The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.
      Graphical abstract image Teaser A synthesized view on oncogenic processes based on PanCancer Atlas analyses highlights the complex impact of genome alterations on the signaling and multi-omic profiles of human cancers as well as their influence on tumor microenvironment.

      PubDate: 2018-04-11T14:59:47Z
       
  • Oncogenic Signaling Pathways in The Cancer Genome Atlas
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Francisco Sanchez-Vega, Marco Mina, Joshua Armenia, Walid K. Chatila, Augustin Luna, Konnor C. La, Sofia Dimitriadoy, David L. Liu, Havish S. Kantheti, Sadegh Saghafinia, Debyani Chakravarty, Foysal Daian, Qingsong Gao, Matthew H. Bailey, Wen-Wei Liang, Steven M. Foltz, Ilya Shmulevich, Li Ding, Zachary Heins, Angelica Ochoa, Benjamin Gross, Jianjiong Gao, Hongxin Zhang, Ritika Kundra, Cyriac Kandoth, Istemi Bahceci, Leonard Dervishi, Ugur Dogrusoz, Wanding Zhou, Hui Shen, Peter W. Laird, Gregory P. Way, Casey S. Greene, Han Liang, Yonghong Xiao, Chen Wang, Antonio Iavarone, Alice H. Berger, Trever G. Bivona, Alexander J. Lazar, Gary D. Hammer, Thomas Giordano, Lawrence N. Kwong, Grant McArthur, Chenfei Huang, Aaron D. Tward, Mitchell J. Frederick, Frank McCormick, Matthew Meyerson, Eliezer M. Van Allen, Andrew D. Cherniack, Giovanni Ciriello, Chris Sander, Nikolaus Schultz
      Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.
      Graphical abstract image Teaser An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.

      PubDate: 2018-04-11T14:59:47Z
       
  • Machine Learning Identifies Stemness Features Associated with Oncogenic
           Dedifferentiation
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Tathiane M. Malta, Artem Sokolov, Andrew J. Gentles, Tomasz Burzykowski, Laila Poisson, John N. Weinstein, Bożena Kamińska, Joerg Huelsken, Larsson Omberg, Olivier Gevaert, Antonio Colaprico, Patrycja Czerwińska, Sylwia Mazurek, Lopa Mishra, Holger Heyn, Alex Krasnitz, Andrew K. Godwin, Alexander J. Lazar, Joshua M. Stuart, Katherine A. Hoadley, Peter W. Laird, Houtan Noushmehr, Maciej Wiznerowicz
      Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.
      Graphical abstract image Teaser Stemness features extracted from transcriptomic and epigenetic data from TCGA tumors reveal novel biological and clinical insight, as well as potential drug targets for anti-cancer therapies.

      PubDate: 2018-04-11T14:59:47Z
       
  • Pathogenic Germline Variants in 10,389 Adult Cancers
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Kuan-lin Huang, R. Jay Mashl, Yige Wu, Deborah I. Ritter, Jiayin Wang, Clara Oh, Marta Paczkowska, Sheila Reynolds, Matthew A. Wyczalkowski, Ninad Oak, Adam D. Scott, Michal Krassowski, Andrew D. Cherniack, Kathleen E. Houlahan, Reyka Jayasinghe, Liang-Bo Wang, Daniel Cui Zhou, Di Liu, Song Cao, Young Won Kim, Amanda Koire, Joshua F. McMichael, Vishwanathan Hucthagowder, Tae-Beom Kim, Abigail Hahn, Chen Wang, Michael D. McLellan, Fahd Al-Mulla, Kimberly J. Johnson, Olivier Lichtarge, Paul C. Boutros, Benjamin Raphael, Alexander J. Lazar, Wei Zhang, Michael C. Wendl, Ramaswamy Govindan, Sanjay Jain, David Wheeler, Shashikant Kulkarni, John F. Dipersio, Jüri Reimand, Funda Meric-Bernstam, Ken Chen, Ilya Shmulevich, Sharon E. Plon, Feng Chen, Li Ding
      We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.
      Graphical abstract image Teaser A pan-cancer analysis identifies hundreds of predisposing germline variants.

      PubDate: 2018-04-11T14:59:47Z
       
  • Comprehensive Characterization of Cancer Driver Genes and Mutations
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Matthew H. Bailey, Collin Tokheim, Eduard Porta-Pardo, Sohini Sengupta, Denis Bertrand, Amila Weerasinghe, Antonio Colaprico, Michael C. Wendl, Jaegil Kim, Brendan Reardon, Patrick Kwok-Shing Ng, Kang Jin Jeong, Song Cao, Zixing Wang, Jianjiong Gao, Qingsong Gao, Fang Wang, Eric Minwei Liu, Loris Mularoni, Carlota Rubio-Perez, Niranjan Nagarajan, Isidro Cortés-Ciriano, Daniel Cui Zhou, Wen-Wei Liang, Julian M. Hess, Venkata D. Yellapantula, David Tamborero, Abel Gonzalez-Perez, Chayaporn Suphavilai, Jia Yu Ko, Ekta Khurana, Peter J. Park, Eliezer M. Van Allen, Han Liang, Michael S. Lawrence, Adam Godzik, Nuria Lopez-Bigas, Josh Stuart, David Wheeler, Gad Getz, Ken Chen, Alexander J. Lazar, Gordon B. Mills, Rachel Karchin, Li Ding
      Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%–85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.
      Graphical abstract image Teaser A comprehensive analysis of oncogenic driver genes and mutations in >9,000 tumors across 33 cancer types highlights the prevalence of clinically actionable cancer driver events in TCGA tumor samples.

      PubDate: 2018-04-11T14:59:47Z
       
  • A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient
           Samples
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Han Chen, Chunyan Li, Xinxin Peng, Zhicheng Zhou, John N. Weinstein, Han Liang
      The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.
      Graphical abstract image Teaser Causal enhancer-target-gene relationships are inferred from a systematic analysis of 33 cancer types.

      PubDate: 2018-04-11T14:59:47Z
       
  • An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality
           Survival Outcome Analytics
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Jianfang Liu, Tara Lichtenberg, Katherine A. Hoadley, Laila M. Poisson, Alexander J. Lazar, Andrew D. Cherniack, Albert J. Kovatich, Christopher C. Benz, Douglas A. Levine, Adrian V. Lee, Larsson Omberg, Denise M. Wolf, Craig D. Shriver, Vesteinn Thorsson, Hai Hu
      For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale.
      Graphical abstract image Teaser Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types.

      PubDate: 2018-04-11T14:59:47Z
       
  • Influenza Infection in Humans Induces Broadly Cross-Reactive and
           Protective Neuraminidase-Reactive Antibodies
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Yao-Qing Chen, Teddy John Wohlbold, Nai-Ying Zheng, Min Huang, Yunping Huang, Karlynn E. Neu, Jiwon Lee, Hongquan Wan, Karla Thatcher Rojas, Ericka Kirkpatrick, Carole Henry, Anna-Karin E. Palm, Christopher T. Stamper, Linda Yu-Ling Lan, David J. Topham, John Treanor, Jens Wrammert, Rafi Ahmed, Maryna C. Eichelberger, George Georgiou, Florian Krammer, Patrick C. Wilson
      Antibodies to the hemagglutinin (HA) and neuraminidase (NA) glycoproteins are the major mediators of protection against influenza virus infection. Here, we report that current influenza vaccines poorly display key NA epitopes and rarely induce NA-reactive B cells. Conversely, influenza virus infection induces NA-reactive B cells at a frequency that approaches (H1N1) or exceeds (H3N2) that of HA-reactive B cells. NA-reactive antibodies display broad binding activity spanning the entire history of influenza A virus circulation in humans, including the original pandemic strains of both H1N1 and H3N2 subtypes. The antibodies robustly inhibit the enzymatic activity of NA, including oseltamivir-resistant variants, and provide robust prophylactic protection, including against avian H5N1 viruses, in vivo. When used therapeutically, NA-reactive antibodies protected mice from lethal influenza virus challenge even 48 hr post infection. These findings strongly suggest that influenza vaccines should be optimized to improve targeting of NA for durable and broad protection against divergent influenza strains.
      Graphical abstract image Teaser Current influenza vaccines predominantly produce antibodies targeting the viral hemagglutinin (HA). However, during natural infection, the body also produces antibodies targeting the viral neuraminidase (NA). These NA antibodies can provide robust and broad protection and could potentially be elicited prophylactically or via new vaccine strategies or used therapeutically.

      PubDate: 2018-04-11T14:59:47Z
       
  • Direct Promoter Repression by BCL11A Controls the Fetal to Adult
           Hemoglobin Switch
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Nan Liu, Victoria V. Hargreaves, Qian Zhu, Jesse V. Kurland, Jiyoung Hong, Woojin Kim, Falak Sher, Claudio Macias-Trevino, Julia M. Rogers, Ryo Kurita, Yukio Nakamura, Guo-Cheng Yuan, Daniel E. Bauer, Jian Xu, Martha L. Bulyk, Stuart H. Orkin
      Fetal hemoglobin (HbF, α2γ2) level is genetically controlled and modifies severity of adult hemoglobin (HbA, α2β2) disorders, sickle cell disease, and β-thalassemia. Common genetic variation affects expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from γ- to β- globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence. This motif appears in embryonic and fetal-expressed globin promoters and is duplicated in γ-globin promoters. The more distal of the duplicated motifs is mutated in individuals with hereditary persistence of HbF. Using the CUT&RUN approach to map protein binding sites in erythroid cells, we demonstrate BCL11A occupancy preferentially at the distal motif, which can be disrupted by editing the promoter. Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching.
      Graphical abstract image Teaser The developmental transition between fetal and adult hemoglobin is controlled by a repressor that acts directly at the γ-globin gene promoter, suggesting a simplified control mechanism that could be manipulated in treatment of γ-hemoglobin disorders.

      PubDate: 2018-04-11T14:59:47Z
       
  • Common PIEZO1 Allele in African Populations Causes RBC Dehydration and
           Attenuates Plasmodium Infection
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Shang Ma, Stuart Cahalan, Gregory LaMonte, Nathan D. Grubaugh, Weizheng Zeng, Swetha E. Murthy, Emma Paytas, Ramya Gamini, Viktor Lukacs, Tess Whitwam, Meaghan Loud, Rakhee Lohia, Laurence Berry, Shahid M. Khan, Chris J. Janse, Michael Bandell, Christian Schmedt, Kai Wengelnik, Andrew I. Su, Eric Honore, Elizabeth A. Winzeler, Kristian G. Andersen, Ardem Patapoutian
      Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection in vitro; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of the African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance.
      Graphical abstract image Teaser A gain-of-function mutation in the mechanically activated channel PIEZO1 is associated with resistance to the malaria parasite Plasmodium falciparum.

      PubDate: 2018-04-11T14:59:47Z
       
  • Flavin Monooxygenase-Generated N-Hydroxypipecolic Acid Is a Critical
           Element of Plant Systemic Immunity
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Michael Hartmann, Tatyana Zeier, Friederike Bernsdorff, Vanessa Reichel-Deland, Denis Kim, Michele Hohmann, Nicola Scholten, Stefan Schuck, Andrea Bräutigam, Torsten Hölzel, Christian Ganter, Jürgen Zeier
      Following a previous microbial inoculation, plants can induce broad-spectrum immunity to pathogen infection, a phenomenon known as systemic acquired resistance (SAR). SAR establishment in Arabidopsis thaliana is regulated by the Lys catabolite pipecolic acid (Pip) and flavin-dependent-monooxygenase1 (FMO1). Here, we show that elevated Pip is sufficient to induce an FMO1-dependent transcriptional reprogramming of leaves that is reminiscent of SAR. In planta and in vitro analyses demonstrate that FMO1 functions as a pipecolate N-hydroxylase, catalyzing the biochemical conversion of Pip to N-hydroxypipecolic acid (NHP). NHP systemically accumulates in plants after microbial attack. When exogenously applied, it overrides the defect of NHP-deficient fmo1 in acquired resistance and acts as a potent inducer of plant immunity to bacterial and oomycete infection. Our work has identified a pathogen-inducible L-Lys catabolic pathway in plants that generates the N-hydroxylated amino acid NHP as a critical regulator of systemic acquired resistance to pathogen infection.
      Graphical abstract image Teaser A pathogen-inducible L-Lys catabolic pathway in plants generates N-hydroxypipecolic acid as a critical regulator of systemic acquired resistance to pathogen infection.

      PubDate: 2018-04-11T14:59:47Z
       
  • Development of Concurrent Retinotopic Maps in the Fly Motion Detection
           Circuit
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Filipe Pinto-Teixeira, Clara Koo, Anthony Michael Rossi, Nathalie Neriec, Claire Bertet, Xin Li, Alberto Del-Valle-Rodriguez, Claude Desplan
      Understanding how complex brain wiring is produced during development is a daunting challenge. In Drosophila, information from 800 retinal ommatidia is processed in distinct brain neuropiles, each subdivided into 800 matching retinotopic columns. The lobula plate comprises four T4 and four T5 neuronal subtypes. T4 neurons respond to bright edge motion, whereas T5 neurons respond to dark edge motion. Each is tuned to motion in one of the four cardinal directions, effectively establishing eight concurrent retinotopic maps to support wide-field motion. We discovered a mode of neurogenesis where two sequential Notch-dependent divisions of either a horizontal or a vertical progenitor produce matching sets of two T4 and two T5 neurons retinotopically coincident with pairwise opposite direction selectivity. We show that retinotopy is an emergent characteristic of this neurogenic program and derives directly from neuronal birth order. Our work illustrates how simple developmental rules can implement complex neural organization.
      Graphical abstract image Teaser The circuit for motion perception emerges out of the developmental program that specifies the identity of neurons.

      PubDate: 2018-04-11T14:59:47Z
       
  • Profound Tissue Specificity in Proliferation Control Underlies Cancer
           Drivers and Aneuploidy Patterns
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Laura Magill Sack, Teresa Davoli, Mamie Z. Li, Yuyang Li, Qikai Xu, Kamila Naxerova, Eric C. Wooten, Ronald J. Bernardi, Timothy D. Martin, Ting Chen, Yumei Leng, Anthony C. Liang, Kathleen A. Scorsone, Thomas F. Westbrook, Kwok-Kin Wong, Stephen J. Elledge
      Genomics has provided a detailed structural description of the cancer genome. Identifying oncogenic drivers that work primarily through dosage changes is a current challenge. Unrestrained proliferation is a critical hallmark of cancer. We constructed modular, barcoded libraries of human open reading frames (ORFs) and performed screens for proliferation regulators in multiple cell types. Approximately 10% of genes regulate proliferation, with most performing in an unexpectedly highly tissue-specific manner. Proliferation drivers in a given cell type showed specific enrichment in somatic copy number changes (SCNAs) from cognate tumors and helped predict aneuploidy patterns in those tumors, implying that tissue-type-specific genetic network architectures underlie SCNA and driver selection in different cancers. In vivo screening confirmed these results. We report a substantial contribution to the catalog of SCNA-associated cancer drivers, identifying 147 amplified and 107 deleted genes as potential drivers, and derive insights about the genetic network architecture of aneuploidy in tumors.
      Graphical abstract image Teaser The highly tissue-specific epigenetic landscape of a given cell type establishes its responsiveness to oncogenic proliferation signals and determines which drivers, somatic copy number changes, and anueploidies are selected during tumorigenesis.

      PubDate: 2018-04-11T14:59:47Z
       
  • Tumor Evolution and Drug Response in Patient-Derived Organoid Models of
           Bladder Cancer
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Suk Hyung Lee, Wenhuo Hu, Justin T. Matulay, Mark V. Silva, Tomasz B. Owczarek, Kwanghee Kim, Chee Wai Chua, LaMont J. Barlow, Cyriac Kandoth, Alanna B. Williams, Sarah K. Bergren, Eugene J. Pietzak, Christopher B. Anderson, Mitchell C. Benson, Jonathan A. Coleman, Barry S. Taylor, Cory Abate-Shen, James M. McKiernan, Hikmat Al-Ahmadie, David B. Solit, Michael M. Shen
      Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
      Graphical abstract image Teaser A biobank of patient-derived bladder tumor organoids faithfully recapitulates features of human cancer and enables analysis of clonal evolution and drug responses.

      PubDate: 2018-04-11T14:59:47Z
       
  • Retraction Notice to: FMN2 Makes Perinuclear Actin to Protect Nuclei
           during Confined Migration and Promote Metastasis
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Colleen T. Skau, Robert S. Fischer, Pinar Gurel, Hawa Racine Thiam, Anthony Tubbs, Michelle A. Baird, Michael W. Davidson, Matthieu Piel, Gregory M. Alushin, Andre Nussenzweig, Patricia S. Steeg, Clare M. Waterman


      PubDate: 2018-04-11T14:59:47Z
       
  • SnapShot: TCGA-Analyzed Tumors
    • Abstract: Publication date: 5 April 2018
      Source:Cell, Volume 173, Issue 2
      Author(s): Amy Blum, Peggy Wang, Jean C. Zenklusen
      This SnapShot provides a list of the tumor types characterized by The Cancer Genome Atlas (TCGA) program. Key findings shown are the most relevant discoveries described in each marker paper for the tumor type.
      Teaser This SnapShot provides a list of the tumor types characterized by The Cancer Genome Atlas (TCGA) program. Key findings shown are the most relevant discoveries described in each marker paper for the tumor type.

      PubDate: 2018-04-11T14:59:47Z
       
  • Visualization of Membrane Pore in Live Cells Reveals a Dynamic-Pore Theory
           Governing Fusion and Endocytosis
    • Abstract: Publication date: Available online 5 April 2018
      Source:Cell
      Author(s): Wonchul Shin, Lihao Ge, Gianvito Arpino, Seth A. Villarreal, Edaeni Hamid, Huisheng Liu, Wei-Dong Zhao, Peter J. Wen, Hsueh-Cheng Chiang, Ling-Gang Wu
      Fusion is thought to open a pore to release vesicular cargoes vital for many biological processes, including exocytosis, intracellular trafficking, fertilization, and viral entry. However, fusion pores have not been observed and thus proved in live cells. Its regulatory mechanisms and functions remain poorly understood. With super-resolution STED microscopy, we observed dynamic fusion pore behaviors in live (neuroendocrine) cells, including opening, expansion, constriction, and closure, where pore size may vary between 0 and 490 nm within 26 milliseconds to seconds (vesicle size: 180–720 nm). These pore dynamics crucially determine the efficiency of vesicular cargo release and vesicle retrieval. They are generated by competition between pore expansion and constriction. Pharmacology and mutation experiments suggest that expansion and constriction are mediated by F-actin-dependent membrane tension and calcium/dynamin, respectively. These findings provide the missing live-cell evidence, proving the fusion-pore hypothesis, and establish a live-cell dynamic-pore theory accounting for fusion, fission, and their regulation.
      Graphical abstract image Teaser The missing live-cell evidence proving the fusion pore hypothesis reveals metastable pores that are two orders of magnitude larger than previously thought and can constrict and close instantly or slowly.

      PubDate: 2018-04-11T14:59:47Z
       
  • Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of
           GDP and GTP
    • Abstract: Publication date: Available online 5 April 2018
      Source:Cell
      Author(s): Qi Hu, Kevan M. Shokat
      The single most frequent cancer-causing mutation across all heterotrimeric G proteins is R201C in Gαs. The current model explaining the gain-of-function activity of the R201 mutations is through the loss of GTPase activity and resulting inability to switch off to the GDP state. Here, we find that the R201C mutation can bypass the need for GTP binding by directly activating GDP-bound Gαs through stabilization of an intramolecular hydrogen bond network. Having found that a gain-of-function mutation can convert GDP into an activator, we postulated that a reciprocal mutation might disrupt the normal role of GTP. Indeed, we found R228C, a loss-of-function mutation in Gαs that causes pseudohypoparathyroidism type 1a (PHP-Ia), compromised the adenylyl cyclase-activating activity of Gαs bound to a non-hydrolyzable GTP analog. These findings show that disease-causing mutations in Gαs can subvert the canonical roles of GDP and GTP, providing new insights into the regulation mechanism of G proteins.
      Graphical abstract image Teaser Frequent pathogenic mutations in G proteins can cause signaling activation by converting GDP into an activator, rather than locking the proteins at a GTP-bound state.

      PubDate: 2018-04-11T14:59:47Z
       
  • Stress Granule Assembly Disrupts Nucleocytoplasmic Transport
    • Abstract: Publication date: Available online 5 April 2018
      Source:Cell
      Author(s): Ke Zhang, J. Gavin Daigle, Kathleen M. Cunningham, Alyssa N. Coyne, Kai Ruan, Jonathan C. Grima, Kelly E. Bowen, Harsh Wadhwa, Peiguo Yang, Frank Rigo, J. Paul Taylor, Aaron D. Gitler, Jeffrey D. Rothstein, Thomas E. Lloyd
      Defects in nucleocytoplasmic transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, nucleocytoplasmic transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts nucleocytoplasmic transport. Here, we show that cellular stress disrupts nucleocytoplasmic transport by localizing critical nucleocytoplasmic transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis. Importantly, inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses nucleocytoplasmic transport defects as well as neurodegeneration in C9ORF72-mediated ALS/FTD. Our findings identify a link between stress granule assembly and nucleocytoplasmic transport, two fundamental cellular processes implicated in the pathogenesis of C9ORF72-mediated ALS/FTD and other neurodegenerative diseases.
      Graphical abstract image Teaser Sequestration of key nucleocytoplasmic transport factors in stress granules exacerbates neurodegeneration, and blocking this aspect of the stress response ameliorates effects in a model of C9-ALS/FTD.

      PubDate: 2018-04-11T14:59:47Z
       
  • A Kinesin-14 Motor Activates Neocentromeres to Promote Meiotic Drive in
           Maize
    • Abstract: Publication date: Available online 5 April 2018
      Source:Cell
      Author(s): R. Kelly Dawe, Elizabeth G. Lowry, Jonathan I. Gent, Michelle C. Stitzer, Kyle W. Swentowsky, David M. Higgins, Jeffrey Ross-Ibarra, Jason G. Wallace, Lisa B. Kanizay, Magdy Alabady, Weihong Qiu, Kuo-Fu Tseng, Na Wang, Zhi Gao, James A. Birchler, Alex E. Harkess, Amy L. Hodges, Evelyn N. Hiatt
      Maize abnormal chromosome 10 (Ab10) encodes a classic example of true meiotic drive that converts heterochromatic regions called knobs into motile neocentromeres that are preferentially transmitted to egg cells. Here, we identify a cluster of eight genes on Ab10, called the Kinesin driver (Kindr) complex, that are required for both neocentromere motility and preferential transmission. Two meiotic drive mutants that lack neocentromere activity proved to be kindr epimutants with increased DNA methylation across the entire gene cluster. RNAi of Kindr induced a third epimutant and corresponding loss of meiotic drive. Kinesin gliding assays and immunolocalization revealed that KINDR is a functional minus-end-directed kinesin that localizes specifically to knobs containing 180 bp repeats. Sequence comparisons suggest that Kindr diverged from a Kinesin-14A ancestor ∼12 mya and has driven the accumulation of > 500 Mb of knob repeats and affected the segregation of thousands of genes linked to knobs on all 10 chromosomes.
      Graphical abstract image Teaser Neocentromere activity in maize relies on a kinesin motor to drive non-Mendelian inheritance.

      PubDate: 2018-04-11T14:59:47Z
       
  • Pseudouridylation of tRNA-Derived Fragments Steers Translational Control
           in Stem Cells
    • Abstract: Publication date: Available online 5 April 2018
      Source:Cell
      Author(s): Nicola Guzzi, Maciej Cieśla, Phuong Cao Thi Ngoc, Stefan Lang, Sonali Arora, Marios Dimitriou, Kristyna Pimková, Mikael N.E. Sommarin, Roberto Munita, Michal Lubas, Yiting Lim, Kazuki Okuyama, Shamit Soneji, Göran Karlsson, Jenny Hansson, Göran Jönsson, Anders H. Lund, Mikael Sigvardsson, Eva Hellström-Lindberg, Andrew C. Hsieh, Cristian Bellodi
      Pseudouridylation (Ψ) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of Ψ remains poorly understood. Here, we show that a Ψ-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the Ψ “writer” PUS7 modifies and activates a novel network of tRNA-derived small fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF-mediated translation regulation, leading to increased protein biosynthesis and defective germ layer specification. Remarkably, dysregulation of this posttranscriptional regulatory circuitry impairs hematopoietic stem cell commitment and is common to aggressive subtypes of human myelodysplastic syndromes. Our findings unveil a critical function of Ψ in directing translation control in stem cells with important implications for development and disease.
      Graphical abstract image Teaser Translational control in stem cells is orchestrated by pseudouridylation of specific tRNA-derived fragments, impacting stem cell commitment during key developmental processes.

      PubDate: 2018-04-11T14:59:47Z
       
  • Tumor-Induced Generation of Splenic Erythroblast-like Ter-Cells Promotes
           Tumor Progression
    • Abstract: Publication date: Available online 29 March 2018
      Source:Cell
      Author(s): Yanmei Han, Qiuyan Liu, Jin Hou, Yan Gu, Yi Zhang, Zhubo Chen, Jia Fan, Weiping Zhou, Shuangjian Qiu, Yonghong Zhang, Tao Dong, Ning Li, Zhengping Jiang, Ha Zhu, Qian Zhang, Yuanwu Ma, Lianfeng Zhang, Qingqing Wang, Yizhi Yu, Nan Li, Xuetao Cao
      Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+CD45−CD71+ phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor β (TGF-β) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells’ tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications.
      Graphical abstract image Teaser A population of immune cells in the erythroid lineage are induced in a mouse model of hepatocellular carcinoma, which promotes tumor progression through artemin production.

      PubDate: 2018-04-11T14:59:47Z
       
  • Evolutionary Convergence of Pathway-Specific Enzyme Expression
           Stoichiometry
    • Abstract: Publication date: Available online 29 March 2018
      Source:Cell
      Author(s): Jean-Benoît Lalanne, James C. Taggart, Monica S. Guo, Lydia Herzel, Ariel Schieler, Gene-Wei Li
      Coexpression of proteins in response to pathway-inducing signals is the founding paradigm of gene regulation. However, it remains unexplored whether the relative abundance of co-regulated proteins requires precise tuning. Here, we present large-scale analyses of protein stoichiometry and corresponding regulatory strategies for 21 pathways and 67–224 operons in divergent bacteria separated by 0.6–2 billion years. Using end-enriched RNA-sequencing (Rend-seq) with single-nucleotide resolution, we found that many bacterial gene clusters encoding conserved pathways have undergone massive divergence in transcript abundance and architectures via remodeling of internal promoters and terminators. Remarkably, these evolutionary changes are compensated post-transcriptionally to maintain preferred stoichiometry of protein synthesis rates. Even more strikingly, in eukaryotic budding yeast, functionally analogous proteins that arose independently from bacterial counterparts also evolved to convergent in-pathway expression. The broad requirement for exact protein stoichiometries despite regulatory divergence provides an unexpected principle for building biological pathways both in nature and for synthetic activities.
      Graphical abstract image Teaser Enzymatic pathways have exquisitely preferred protein expression stoichiometry that is conserved across broad evolutionary lineages despite many opportunities to diverge due to changes in sequence and regulation.

      PubDate: 2018-04-11T14:59:47Z
       
  • A Huntingtin Knockin Pig Model Recapitulates Features of Selective
           Neurodegeneration in Huntington’s Disease
    • Abstract: Publication date: Available online 29 March 2018
      Source:Cell
      Author(s): Sen Yan, Zhuchi Tu, Zhaoming Liu, Nana Fan, Huiming Yang, Su Yang, Weili Yang, Yu Zhao, Zhen Ouyang, Chengdan Lai, Huaqiang Yang, Li Li, Qishuai Liu, Hui Shi, Guangqing Xu, Heng Zhao, Hongjiang Wei, Zhong Pei, Shihua Li, Liangxue Lai, Xiao-Jiang Li
      Huntington’s disease (HD) is characterized by preferential loss of the medium spiny neurons in the striatum. Using CRISPR/Cas9 and somatic nuclear transfer technology, we established a knockin (KI) pig model of HD that endogenously expresses full-length mutant huntingtin (HTT). By breeding this HD pig model, we have successfully obtained F1 and F2 generation KI pigs. Characterization of founder and F1 KI pigs shows consistent movement, behavioral abnormalities, and early death, which are germline transmittable. More importantly, brains of HD KI pig display striking and selective degeneration of striatal medium spiny neurons. Thus, using a large animal model of HD, we demonstrate for the first time that overt and selective neurodegeneration seen in HD patients can be recapitulated by endogenously expressed mutant proteins in large mammals, a finding that also underscores the importance of using large mammals to investigate the pathogenesis of neurodegenerative diseases and their therapeutics.
      Graphical abstract image Teaser A CRISPR/Cas9 knockin pig model recapitulates the selective neurodegeneration observed in human Huntington’s disease patients.

      PubDate: 2018-04-11T14:59:47Z
       
  • Fetal Neuropathology in Zika Virus-Infected Pregnant Female Rhesus Monkeys
    • Abstract: Publication date: Available online 29 March 2018
      Source:Cell
      Author(s): Amanda J. Martinot, Peter Abbink, Onur Afacan, Anna K. Prohl, Roderick Bronson, Jonathan L. Hecht, Erica N. Borducchi, Rafael A. Larocca, Rebecca L. Peterson, William Rinaldi, Melissa Ferguson, Peter J. Didier, Deborah Weiss, Mark G. Lewis, Rafael A. De La Barrera, Edward Yang, Simon K. Warfield, Dan H. Barouch
      The development of interventions to prevent congenital Zika syndrome (CZS) has been limited by the lack of an established nonhuman primate model. Here we show that infection of female rhesus monkeys early in pregnancy with Zika virus (ZIKV) recapitulates many features of CZS in humans. We infected 9 pregnant monkeys with ZIKV, 6 early in pregnancy (weeks 6–7 of gestation) and 3 later in pregnancy (weeks 12–14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys infected early in pregnancy exhibited prolonged maternal viremia and fetal neuropathology, including fetal loss, smaller brain size, and histopathologic brain lesions, including microcalcifications, hemorrhage, necrosis, vasculitis, gliosis, and apoptosis of neuroprogenitor cells. High-resolution MRI demonstrated concordant lesions indicative of deep gray matter injury. We also observed spinal, ocular, and neuromuscular pathology. Our data show that vascular compromise and neuroprogenitor cell dysfunction are hallmarks of CZS pathogenesis, suggesting novel strategies to prevent and to treat this disease.
      Graphical abstract image Teaser ZIKV infection in early pregnant female rhesus monkeys resulted in fetal neuropathology with vascular compromise and neuroprogenitor cell dysfunction, similar to congenital ZIKV syndrome in human infants.

      PubDate: 2018-04-11T14:59:47Z
       
  • There Will Be Blood Tests
    • Abstract: Publication date: 22 March 2018
      Source:Cell, Volume 173, Issue 1
      Author(s): Stacie E. Dodgson


      PubDate: 2018-04-11T14:59:47Z
       
  • Gene Therapy for Retinal Degeneration
    • Abstract: Publication date: 22 March 2018
      Source:Cell, Volume 173, Issue 1
      Author(s): Rajendra S. Apte
      Biallelic mutations in the RPE65 gene are associated with inherited retinal degenerations/dystrophies (IRD) and disrupt the visual cycle, leading to loss of vision. A new adenoviral vector-based gene therapy surgically delivered to retinal cells provides normal human RPE65 protein that can restore the visual cycle and some vision. To view this Bench to Bedside, open or download the PDF.
      Teaser Biallelic mutations in the RPE65 gene are associated with inherited retinal degenerations/dystrophies (IRD) and disrupt the visual cycle, leading to loss of vision. A new adenoviral vector-based gene therapy surgically delivered to retinal cells provides normal human RPE65 protein that can restore the visual cycle and some vision. To view this Bench to Bedside, open or download the PDF.

      PubDate: 2018-04-11T14:59:47Z
       
  • The Predecessors Within . . .
    • Abstract: Publication date: 22 March 2018
      Source:Cell, Volume 173, Issue 1
      Author(s): Benjamin Vernot, Svante Pääbo
      By examining the genomes of present-day people from Asia, researchers show that modern humans met and interbred with Denisovans, distant relatives to Neanderthals, on at least two occasions. As a result, people today carry DNA from two different Denisovan populations.
      Teaser By examining the genomes of present-day people from Asia, researchers show that modern humans met and interbred with Denisovans, distant relatives to Neanderthals, on at least two occasions. As a result, people today carry DNA from two different Denisovan populations.

      PubDate: 2018-04-11T14:59:47Z
       
  • H2S to Mitigate Vascular Aging: A SIRT1 Connection
    • Abstract: Publication date: 22 March 2018
      Source:Cell, Volume 173, Issue 1
      Author(s): Thiruma V. Arumugam, Brian K. Kennedy
      H2S is an endogenous gasotransmitter that plays an important role in physiological conditions. In this issue, Das et al. provide evidence that SIRT1-dependent angiogenesis is augmented by H2S—findings reinforced by Longchamp et al., who demonstrate that H2S-dependent angiogenesis is triggered by amino acid deprivation.
      Teaser H2S is an endogenous gasotransmitter that plays an important role in physiological conditions. In this issue, Das et al. provide evidence that SIRT1-dependent angiogenesis is augmented by H2S—findings reinforced by Longchamp et al., who demonstrate that H2S-dependent angiogenesis is triggered by amino acid deprivation.

      PubDate: 2018-04-11T14:59:47Z
       
  • Opportunities and Challenges in Building a Spatiotemporal Multi-scale
           Model of the Human Pancreatic β Cell
    • Abstract: Publication date: 22 March 2018
      Source:Cell, Volume 173, Issue 1
      Author(s): Jitin Singla, Kyle M. McClary, Kate L. White, Frank Alber, Andrej Sali, Raymond C. Stevens
      The construction of a predictive model of an entire eukaryotic cell that describes its dynamic structure from atomic to cellular scales is a grand challenge at the intersection of biology, chemistry, physics, and computer science. Having such a model will open new dimensions in biological research and accelerate healthcare advancements. Developing the necessary experimental and modeling methods presents abundant opportunities for a community effort to realize this goal. Here, we present a vision for creation of a spatiotemporal multi-scale model of the pancreatic β–cell, a relevant target for understanding and modulating the pathogenesis of diabetes.
      Teaser What will it take to model a cell, fully capturing its structural and functional detail and complexity' This Perspective considers how sciences and technology will need to evolve to do it.

      PubDate: 2018-04-11T14:59:47Z
       
  • Metazoan MicroRNAs
    • Abstract: Publication date: 22 March 2018
      Source:Cell, Volume 173, Issue 1
      Author(s): David P. Bartel
      MicroRNAs (miRNAs) are ∼22 nt RNAs that direct posttranscriptional repression of mRNA targets in diverse eukaryotic lineages. In humans and other mammals, these small RNAs help sculpt the expression of most mRNAs. This article reviews advances in our understanding of the defining features of metazoan miRNAs and their biogenesis, genomics, and evolution. It then reviews how metazoan miRNAs are regulated, how they recognize and cause repression of their targets, and the biological functions of this repression, with a compilation of knockout phenotypes that shows that important biological functions have been identified for most of the broadly conserved miRNAs of mammals.
      Teaser MicroRNAs are pervasive sculptors of gene expression in animals. This review describes these small regulatory RNAs and their biogenesis, regulation, target recognition, mechanism of action, evolution, and biological functions.

      PubDate: 2018-04-11T14:59:47Z
       
  • Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible
           Cause of Vascular Aging
    • Abstract: Publication date: 22 March 2018
      Source:Cell, Volume 173, Issue 1
      Author(s): Abhirup Das, George X. Huang, Michael S. Bonkowski, Alban Longchamp, Catherine Li, Michael B. Schultz, Lynn-Jee Kim, Brenna Osborne, Sanket Joshi, Yuancheng Lu, Jose Humberto Treviño-Villarreal, Myung-Jin Kang, Tzong-tyng Hung, Brendan Lee, Eric O. Williams, Masaki Igarashi, James R. Mitchell, Lindsay E. Wu, Nigel Turner, Zolt Arany, Leonard Guarente, David A. Sinclair
      A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1–SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.
      Graphical abstract image Teaser Endothelial SIRT1 regulates pro-angiogenic signals secreted from myocytes and improves muscle health. Treatment of mice with NAD precursor nicotinamide mononucleotide improves vascular and increases endurance in aging mice.

      PubDate: 2018-04-11T14:59:47Z
       
  • B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique
           Vulnerability in B Cell Malignancies
    • Authors: Gang Xiao; Lai N. Chan; Lars Klemm; Daniel Braas; Zhengshan Chen; Huimin Geng; Qiuyi Chen Zhang; Ali Aghajanirefah; Kadriye Nehir Cosgun; Teresa Sadras; Jaewoong Lee; Tamara Mirzapoiazova; Ravi Salgia; Thomas Ernst; Andreas Hochhaus; Hassan Jumaa; Xiaoyan Jiang; David M. Weinstock; Thomas G. Graeber; Markus Müschen
      Abstract: Publication date: Available online 15 March 2018
      Source:Cell
      Author(s): Gang Xiao, Lai N. Chan, Lars Klemm, Daniel Braas, Zhengshan Chen, Huimin Geng, Qiuyi Chen Zhang, Ali Aghajanirefah, Kadriye Nehir Cosgun, Teresa Sadras, Jaewoong Lee, Tamara Mirzapoiazova, Ravi Salgia, Thomas Ernst, Andreas Hochhaus, Hassan Jumaa, Xiaoyan Jiang, David M. Weinstock, Thomas G. Graeber, Markus Müschen
      B cell activation during normal immune responses and oncogenic transformation impose increased metabolic demands on B cells and their ability to retain redox homeostasis. While the serine/threonine-protein phosphatase 2A (PP2A) was identified as a tumor suppressor in multiple types of cancer, our genetic studies revealed an essential role of PP2A in B cell tumors. Thereby, PP2A redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) to salvage oxidative stress. This unique vulnerability reflects constitutively low PPP activity in B cells and transcriptional repression of G6PD and other key PPP enzymes by the B cell transcription factors PAX5 and IKZF1. Reflecting B-cell-specific transcriptional PPP-repression, glucose carbon utilization in B cells is heavily skewed in favor of glycolysis resulting in lack of PPP-dependent antioxidant protection. These findings reveal a gatekeeper function of the PPP in a broad range of B cell malignancies that can be efficiently targeted by small molecule inhibition of PP2A and G6PD.
      Graphical abstract image Teaser PP2A redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway to salvage oxidative stress in B cell tumors.

      PubDate: 2018-03-19T11:28:30Z
      DOI: 10.1016/j.cell.2018.02.048
       
  • Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced
           Proteotoxicity
    • Authors: Kayatekin Audra; Amasino Giorgio Gaglia Jason Flannick Julia Bonner Saranna
      Abstract: Publication date: Available online 8 March 2018
      Source:Cell
      Author(s): Can Kayatekin, Audra Amasino, Giorgio Gaglia, Jason Flannick, Julia M. Bonner, Saranna Fanning, Priyanka Narayan, M. Inmaculada Barrasa, David Pincus, Dirk Landgraf, Justin Nelson, William R. Hesse, Michael Costanzo, Chad L. Myers, Charles Boone, Jose C. Florez, Susan Lindquist
      Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to β cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to degrade peptides stuck within the translocon between the cytoplasm and the endoplasmic reticulum, was the strongest suppressor of IAPP toxicity. By testing variants of the human homolog, ZMPSTE24, with varying activity levels, the rescue of IAPP toxicity proved to be directly proportional to the declogging efficiency. Clinically relevant ZMPSTE24 variants identified in the largest database of exomes sequences derived from T2D patients were characterized using the yeast model, revealing 14 partial loss-of-function variants, which were enriched among diabetes patients over 2-fold. Thus, clogging of the translocon by IAPP oligomers may contribute to β cell failure.
      Graphical abstract image Teaser A combination of yeast- and human-genetics studies explains how aggregates of human islet amyloid polypeptide interfere with protein translocon function to drive β cell dysfunction in type 2 diabetes.

      PubDate: 2018-03-19T11:28:30Z
       
 
 
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