for Journals by Title or ISSN
for Articles by Keywords
help
Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [680 followers]  Follow
    
   Full-text available via subscription Subscription journal  (Not entitled to full-text)
   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3039 journals]
  • Cancer: The Road Ahead
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): The editorial team


      PubDate: 2017-02-15T13:02:02Z
       
  • Metastasis: Slipping Control
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Xiaohong Helena Yang


      PubDate: 2017-02-15T13:02:02Z
       
  • Getting Data Sharing Right to Help Fulfill the Promise of Cancer Genomics
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Neil Savage
      Limited access to the profusion of sequence information derived from cancer patients worldwide stymies basic research and clinical decisions. Efforts are underway to streamline and safeguard data use.
      Teaser Limited access to the profusion of sequence information derived from cancer patients worldwide stymies basic research and clinical decisions. Efforts are underway to streamline and safeguard data use.

      PubDate: 2017-02-15T13:02:02Z
       
  • PDGFRA Antibody for Soft Tissue Sarcoma
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Lillian R. Klug, Michael C. Heinrich
      Lartruvo (olaratumab) is a monoclonal antibody against the extracellular domain of PDGFRA. Olaratumab blocks ligand binding and thereby inhibits activation of PDGFRA kinase activity. Pre-clinically, this antibody inhibited PDGFRA-dependent tumor growth. In a randomized Phase II study, adding olaratumab to doxorubicin chemotherapy significantly improved overall survival, leading to FDA approval.
      Teaser Lartruvo (olaratumab) is a monoclonal antibody against the extracellular domain of PDGFRA. Olaratumab blocks ligand binding and thereby inhibits activation of PDGFRA kinase activity. Pre-clinically, this antibody inhibited PDGFRA-dependent tumor growth. In a randomized Phase II study, adding olaratumab to doxorubicin chemotherapy significantly improved overall survival, leading to FDA approval.

      PubDate: 2017-02-15T13:02:02Z
       
  • Poisoning the Devil
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Zhu Chen, Sai-Juan Chen


      PubDate: 2017-02-15T13:02:02Z
       
  • A Convergence of Genetics and Epigenetics in Cancer
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      What is at the forefront of the intersection of genetics and epigenetics in cancer and how do we use what we’ve learned to devise new cures' These are the questions Cell editor Jiaying Tan posed to Jan Korbel and Charles Roberts. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.
      Teaser What is at the forefront of the intersection of genetics and epigenetics in cancer and how do we use what we’ve learned to devise new cures' These are the questions Cell editor Jiaying Tan posed to Jan Korbel and Charles Roberts. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.

      PubDate: 2017-02-15T13:02:02Z
       
  • Where is the Future of Drug Discovery for Cancer'
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      With both small molecules and biologics succeeding in trials and in the clinic, the scope of drug discovery in cancer is changing. We asked a group of researchers to share their visions for how to identify new targets and how to approach taming them.
      Teaser With both small molecules and biologics succeeding in trials and in the clinic, the scope of drug discovery in cancer is changing. We asked a group of researchers to share their visions for how to identify new targets and how to approach taming them.

      PubDate: 2017-02-15T13:02:02Z
       
  • Translating Germline Cancer Risk into Precision Prevention
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Matthew B. Yurgelun, Georgia Chenevix-Trench, Scott M. Lippman
      Study of the biology of tumors caused by germline mutations has led to recent paradigm-changing therapy and is driving precision prevention efforts, including immune oncology and early detection research. Here, we explore recent biologic advances that are redefining the spectrum of cancers linked to various hereditary predisposition syndromes and can be leveraged to improve personalized risk assessment and develop novel interventions to prevent or intercept cancer.
      Teaser Study of the biology of tumors caused by germline mutations has led to recent paradigm-changing therapy and is driving precision prevention efforts, including immune oncology and early detection research. Here, we explore recent biologic advances that are redefining the spectrum of cancers linked to various hereditary predisposition syndromes and can be leveraged to improve personalized risk assessment and develop novel interventions to prevent or intercept cancer.

      PubDate: 2017-02-15T13:02:02Z
       
  • Next-Generation Sequencing of Circulating Tumor DNA for Early Cancer
           Detection
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Alexander M. Aravanis, Mark Lee, Richard D. Klausner
      Curative therapies are most successful when cancer is diagnosed and treated at an early stage. We advocate that technological advances in next-generation sequencing of circulating, tumor-derived nucleic acids hold promise for addressing the challenge of developing safe and effective cancer screening tests.
      Teaser Curative therapies are most successful when cancer is diagnosed and treated at an early stage. We advocate that technological advances in next-generation sequencing of circulating, tumor-derived nucleic acids hold promise for addressing the challenge of developing safe and effective cancer screening tests.

      PubDate: 2017-02-15T13:02:02Z
       
  • Cancer Clinical Trials: The Rear-View Mirror and the Crystal Ball
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Dave Cescon, Lillian L. Siu
      Clinical trials are key to translating scientific advances into progress in cancer research and care. Confronted by developments in basic science, the landscape of clinical cancer research is rapidly evolving. Here, we review recent changes in clinical trials’ design and conduct, and we forecast future directions toward personalized and global impact.
      Teaser Clinical trials are key to translating scientific advances into progress in cancer research and care. Confronted by developments in basic science, the landscape of clinical cancer research is rapidly evolving. Here, we review recent changes in clinical trials’ design and conduct, and we forecast future directions toward personalized and global impact.

      PubDate: 2017-02-15T13:02:02Z
       
  • How Much Longer Will We Put Up With $100,000 Cancer Drugs'
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Paul Workman, Giulio F. Draetta, Jan H.M. Schellens, René Bernards
      The spiraling cost of new drugs mandates a fundamentally different approach to keep lifesaving therapies affordable for cancer patients. We call here for the formation of new relationships between academic drug discovery centers and commercial partners, which can accelerate the development of truly transformative drugs at sustainable prices.
      Teaser The spiraling cost of new drugs mandates a fundamentally different approach to keep lifesaving therapies affordable for cancer patients. We call here for the formation of new relationships between academic drug discovery centers and commercial partners, which can accelerate the development of truly transformative drugs at sustainable prices.

      PubDate: 2017-02-15T13:02:02Z
       
  • Implementing Genome-Driven Oncology
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): David M. Hyman, Barry S. Taylor, José Baselga
      Early successes in identifying and targeting individual oncogenic drivers, together with the increasing feasibility of sequencing tumor genomes, have brought forth the promise of genome-driven oncology care. As we expand the breadth and depth of genomic analyses, the biological and clinical complexity of its implementation will be unparalleled. Challenges include target credentialing and validation, implementing drug combinations, clinical trial designs, targeting tumor heterogeneity, and deploying technologies beyond DNA sequencing, among others. We review how contemporary approaches are tackling these challenges and will ultimately serve as an engine for biological discovery and increase our insight into cancer and its treatment.
      Teaser The era of precision oncology is driven by increased feasibility of sequencing tumor genomes and improving target validation as well as drug combinations for patient-specific treatment.

      PubDate: 2017-02-15T13:02:02Z
       
  • Applications of Immunogenomics to Cancer
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): X. Shirley Liu, Elaine R. Mardis
      Cancer immunogenomics originally was framed by research supporting the hypothesis that cancer mutations generated novel peptides seen as “non-self” by the immune system. The search for these “neoantigens” has been facilitated by the combination of new sequencing technologies, specialized computational analyses, and HLA binding predictions that evaluate somatic alterations in a cancer genome and interpret their ability to produce an immune-stimulatory peptide. The resulting information can characterize a tumor’s neoantigen load, its cadre of infiltrating immune cell types, the T or B cell receptor repertoire, and direct the design of a personalized therapeutic.
      Teaser The development of new high-throughput technologies facilitates the application of immunogenomics to cancer.

      PubDate: 2017-02-15T13:02:02Z
       
  • Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Nicholas McGranahan, Charles Swanton
      Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Here, we review data and technologies that have revealed intra-tumor heterogeneity across cancer types and the dynamics, constraints, and contingencies inherent to tumor evolution. We emphasize the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations, in driving tumor evolution and metastasis and consider the role of the tumor microenvironment in engendering heterogeneity and drug resistance. We suggest that bold approaches to drug development, harnessing the adaptive properties of the immune-microenvironment while limiting those of the tumor, combined with advances in clinical trial-design, will improve patient outcome.
      Teaser Cancer cells interact with each other and with the microenvironment, fostering tumor diversity and evolution. This Review discusses the etiology and clinical implications of intra-tumor heterogeneity and outlines novel therapeutic approaches that account for tumor diversity and evolution.

      PubDate: 2017-02-15T13:02:02Z
       
  • Transcriptional Addiction in Cancer
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): James E. Bradner, Denes Hnisz, Richard A. Young
      Cancer arises from genetic alterations that invariably lead to dysregulated transcriptional programs. These dysregulated programs can cause cancer cells to become highly dependent on certain regulators of gene expression. Here, we discuss how transcriptional control is disrupted by genetic alterations in cancer cells, why transcriptional dependencies can develop as a consequence of dysregulated programs, and how these dependencies provide opportunities for novel therapeutic interventions in cancer.
      Teaser Gene dysregulation in cancer cells leads to tumor-specific transcriptional dependencies that can be targeted by a new generation of anti-cancer drugs.

      PubDate: 2017-02-15T13:02:02Z
       
  • Endogenous DNA Damage as a Source of Genomic Instability in Cancer
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Anthony Tubbs, André Nussenzweig
      Genome instability, defined as higher than normal rates of mutation, is a double-edged sword. As a source of genetic diversity and natural selection, mutations are beneficial for evolution. On the other hand, genomic instability can have catastrophic consequences for age-related diseases such as cancer. Mutations arise either from inactivation of DNA repair pathways or in a repair-competent background due to genotoxic stress from celluar processes such as transcription and replication that overwhelm high-fidelity DNA repair. Here, we review recent studies that shed light on endogenous sources of mutation and epigenomic features that promote genomic instability during cancer evolution.
      Teaser Genome instability, defined as higher than normal rates of mutation, is a double-edged sword. As a source of genetic diversity and natural selection, mutations are beneficial for evolution. On the other hand, genomic instability can have catastrophic consequences for age-related diseases such as cancer. Mutations arise either from inactivation of DNA repair pathways or in a repair-competent background due to genotoxic stress from celluar processes such as transcription and replication that overwhelm high-fidelity DNA repair. Here, we review recent studies that shed light on endogenous sources of mutation and epigenomic features that promote genomic instability during cancer evolution.

      PubDate: 2017-02-15T13:02:02Z
       
  • Understanding the Intersections between Metabolism and Cancer Biology
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Matthew G. Vander Heiden, Ralph J. DeBerardinis
      Transformed cells adapt metabolism to support tumor initiation and progression. Specific metabolic activities can participate directly in the process of transformation or support the biological processes that enable tumor growth. Exploiting cancer metabolism for clinical benefit requires defining the pathways that are limiting for cancer progression and understanding the context specificity of metabolic preferences and liabilities in malignant cells. Progress toward answering these questions is providing new insight into cancer biology and can guide the more effective targeting of metabolism to help patients.
      Teaser Emerging evidence highlights the diverse paths for metabolic activities to contribute to cancer development and therapeutic resistance. Understanding the context specificity in the multilayer complexity of cancer metabolism may guide future development in cancer treatment.

      PubDate: 2017-02-15T13:02:02Z
       
  • Emerging Biological Principles of Metastasis
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Arthur W. Lambert, Diwakar R. Pattabiraman, Robert A. Weinberg
      Metastases account for the great majority of cancer-associated deaths, yet this complex process remains the least understood aspect of cancer biology. As the body of research concerning metastasis continues to grow at a rapid rate, the biological programs that underlie the dissemination and metastatic outgrowth of cancer cells are beginning to come into view. In this review we summarize the cellular and molecular mechanisms involved in metastasis, with a focus on carcinomas where the most is known, and we highlight the general principles of metastasis that have begun to emerge.
      Teaser Metastatic growth is responsible for a majority of cancer-related deaths and understanding the cellular and molecular mechanisms driving it will yield new insights toward approaching cancer therapies.

      PubDate: 2017-02-15T13:02:02Z
       
  • Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress
           in Cancer
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Juan R. Cubillos-Ruiz, Sarah E. Bettigole, Laurie H. Glimcher
      Malignant cells utilize diverse strategies that enable them to thrive under adverse conditions while simultaneously inhibiting the development of anti-tumor immune responses. Hostile microenvironmental conditions within tumor masses, such as nutrient deprivation, oxygen limitation, high metabolic demand, and oxidative stress, disturb the protein-folding capacity of the endoplasmic reticulum (ER), thereby provoking a cellular state of “ER stress.” Sustained activation of ER stress sensors endows malignant cells with greater tumorigenic, metastatic, and drug-resistant capacity. Additionally, recent studies have uncovered that ER stress responses further impede the development of protective anti-cancer immunity by manipulating the function of myeloid cells in the tumor microenvironment. Here, we discuss the tumorigenic and immunoregulatory effects of ER stress in cancer, and we explore the concept of targeting ER stress responses to enhance the efficacy of standard chemotherapies and evolving cancer immunotherapies in the clinic.
      Teaser The activation of ER stress pathways endows cancer cells with metastatic and drug-resistance capacities through a number of distinct mechanisms. Targeting these pathways offers potential opportunities to enhance the efficacy of chemotherapy and immunotherapies in the clinic.

      PubDate: 2017-02-15T13:02:02Z
       
  • Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Padmanee Sharma, Siwen Hu-Lieskovan, Jennifer A. Wargo, Antoni Ribas
      Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.
      Teaser Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.

      PubDate: 2017-02-15T13:02:02Z
       
  • The Principles of Engineering Immune Cells to Treat Cancer
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Wendell A. Lim, Carl H. June
      Chimeric antigen receptor (CAR) T cells have proven that engineered immune cells can serve as a powerful new class of cancer therapeutics. Clinical experience has helped to define the major challenges that must be met to make engineered T cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors. The emergence of synthetic biology approaches for cellular engineering is providing us with a broadly expanded set of tools for programming immune cells. We discuss how these tools could be used to design the next generation of smart T cell precision therapeutics.
      Teaser The emergence of synthetic biology approaches for cellular engineering is providing us with a broadly expanded set of tools that can be used to design the next generation of smart T cell precision therapeutics for cancer.

      PubDate: 2017-02-15T13:02:02Z
       
  • SnapShot: Circulating Tumor Cells
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Caroline Dive, Ged Brady
      Circulating tumor cells in the blood of patients are both signal flares for the existence of a tumor and harbingers of metastasis. With recent technological developments, these cells can be isolated and analyzed to provide insights into the biology of cancer spread and response to therapy and to offer new avenues for blood biomarker development.
      Teaser Circulating tumor cells in the blood of patients are both signal flares for the existence of a tumor and harbingers of metastasis. With recent technological developments, these cells can be isolated and analyzed to provide insights into the biology of cancer spread and response to therapy and to offer new avenues for blood biomarker development.

      PubDate: 2017-02-15T13:02:02Z
       
  • Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal
           Interactions with Oncogenic Ras
    • Abstract: Publication date: Available online 2 February 2017
      Source:Cell
      Author(s): Tim Wang, Haiyan Yu, Nicholas W. Hughes, Bingxu Liu, Arek Kendirli, Klara Klein, Walter W. Chen, Eric S. Lander, David M. Sabatini
      The genetic dependencies of human cancers widely vary. Here, we catalog this heterogeneity and use it to identify functional gene interactions and genotype-dependent liabilities in cancer. By using genome-wide CRISPR-based screens, we generate a gene essentiality dataset across 14 human acute myeloid leukemia (AML) cell lines. Sets of genes with correlated patterns of essentiality across the lines reveal new gene relationships, the essential substrates of enzymes, and the molecular functions of uncharacterized proteins. Comparisons of differentially essential genes between Ras-dependent and -independent lines uncover synthetic lethal partners of oncogenic Ras. Screens in both human AML and engineered mouse pro-B cells converge on a surprisingly small number of genes in the Ras processing and MAPK pathways and pinpoint PREX1 as an AML-specific activator of MAPK signaling. Our findings suggest general strategies for defining mammalian gene networks and synthetic lethal interactions by exploiting the natural genetic and epigenetic diversity of human cancer cells.
      Graphical abstract image Teaser Charting global genetic interaction networks in human cells with CRISPR-based screens uncovers key Ras interactors.

      PubDate: 2017-02-09T08:33:05Z
       
  • Engineering a Biological Revolution
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Susan Matheson
      The new field of synthetic biology promises to change health care, computer technology, the production of biofuels, and more. Students participating in the International Genetically Engineered Machine (iGEM) competition are on the front lines of this revolution.
      Teaser The new field of synthetic biology promises to change health care, computer technology, the production of biofuels, and more. Students participating in the International Genetically Engineered Machine (iGEM) competition are on the front lines of this revolution.

      PubDate: 2017-01-27T16:45:20Z
       
  • From Durban to the World
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Stephen C. Harrison


      PubDate: 2017-01-27T16:45:20Z
       
  • The Long Tail of mRNA Regulation
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Long stretches of RNA trail after the coding region in most eukaryotic mRNAs. These 3′ untranslated regions (3′ UTRs) hold the key for many aspects of regulated gene expression, influencing mRNA stability, protein synthesis, and ultimately protein function. Lara Szewczak asked Rachel Green, Ian Macrae, and Christine Mayr about how dynamic regulation by proteins and microRNAs works within 3′ UTRs. An annotated excerpt of the conversation appears below, and the full conversation is available with the article online.
      Teaser Long stretches of RNA trail after the coding region in most eukaryotic mRNAs. These 3′ untranslated regions (3′ UTRs) hold the key for many aspects of regulated gene expression, influencing mRNA stability, protein synthesis, and ultimately protein function. Lara Szewczak asked Rachel Green, Ian Macrae, and Christine Mayr about how dynamic regulation by proteins and microRNAs works within 3′ UTRs. An annotated excerpt of the conversation appears below, and the full conversation is available with the article online.

      PubDate: 2017-01-27T16:45:20Z
       
  • A Receptor on Acid
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Qiuyan Chen, John J.G. Tesmer
      Wacker et al. report the crystal structure of LSD in complex with one of its major targets in the brain, the 5-HT2B receptor, the first such structure for any psychedelic drug. The results shed light on the molecular mechanisms underlying its ability to induce hallucinations with greater duration and potency than closely related compounds.
      Teaser Wacker et al. report the crystal structure of LSD in complex with one of its major targets in the brain, the 5-HT2B receptor, the first such structure for any psychedelic drug. The results shed light on the molecular mechanisms underlying its ability to induce hallucinations with greater duration and potency than closely related compounds.

      PubDate: 2017-01-27T16:45:20Z
       
  • Cryo-EM Captures the Dynamics of Ion Channel Opening
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): John L. Rubinstein
      In this issue of Cell, Hite and MacKinnon (2017) report the open conformation structure of Slo2.2, a neuronal Na+-activated K+ channel. More importantly, 3D classification of electron cryomicroscopy (cryo-EM) images allows visualization of the structural transition that occurs as the open probability of individual channels increases with added sodium.
      Teaser In this issue of Cell, Hite and MacKinnon (2017) report the open conformation structure of Slo2.2, a neuronal Na+-activated K+ channel. More importantly, 3D classification of electron cryomicroscopy (cryo-EM) images allows visualization of the structural transition that occurs as the open probability of individual channels increases with added sodium.

      PubDate: 2017-01-27T16:45:20Z
       
  • A Red Carpet for Iron Metabolism
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Martina U. Muckenthaler, Stefano Rivella, Matthias W. Hentze, Bruno Galy
      200 billion red blood cells (RBCs) are produced every day, requiring more than 2 × 1015 iron atoms every second to maintain adequate erythropoiesis. These numbers translate into 20 mL of blood being produced each day, containing 6 g of hemoglobin and 20 mg of iron. These impressive numbers illustrate why the making and breaking of RBCs is at the heart of iron physiology, providing an ideal context to discuss recent progress in understanding the systemic and cellular mechanisms that underlie the regulation of iron homeostasis and its disorders.
      Teaser The regulation of iron homeostasis and its related disorders arise from interwoven systemic and cellular mechanisms.

      PubDate: 2017-01-27T16:45:20Z
       
  • The Stromal Intervention: Regulation of Immunity and Inflammation at the
           Epithelial-Mesenchymal Barrier
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Roni Nowarski, Ruaidhrí Jackson, Richard A. Flavell
      The immune system safeguards organ integrity by employing a balancing act of inflammatory and immunosuppressive mechanisms designed to neutralize foreign invaders and resolve injury. Maintaining or restoring a state of immune homeostasis is particularly challenging at barrier sites where constant exposure to immunogenic environmental agents may induce destructive inflammation. Recent studies underscore the role of epithelial and mesenchymal barrier cells in regulating immune cell function and local homeostatic and inflammatory responses. Here, we highlight immunoregulatory circuits engaging epithelial and mesenchymal cells in the intestine, airways, and skin and discuss how immune communications with hematopoietic cells and the microbiota orchestrate local immune homeostasis and inflammation.
      Teaser Recent work underscores the role of the stromal component of different tissues—epithelial and mesenchymal cells—in regulating immune cell function, local tissue homeostasis, and inflammatory response during disease states.

      PubDate: 2017-01-27T16:45:20Z
       
  • Crystal Structure of an LSD-Bound Human Serotonin Receptor
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Daniel Wacker, Sheng Wang, John D. McCorvy, Robin M. Betz, A.J. Venkatakrishnan, Anat Levit, Katherine Lansu, Zachary L. Schools, Tao Che, David E. Nichols, Brian K. Shoichet, Ron O. Dror, Bryan L. Roth
      The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD’s key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR—a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD’s slow binding kinetics may be due to a “lid” formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD’s binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD’s actions at human serotonin receptors. PaperClip
      Graphical abstract image Teaser The structure of LSD with a serotonin receptor reveals the basis for its long-lasting effects and suggests ways to selectively alter receptor signaling.

      PubDate: 2017-01-27T16:45:20Z
       
  • The In Vivo Architecture of the Exocyst Provides Structural Basis for
           Exocytosis
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Andrea Picco, Ibai Irastorza-Azcarate, Tanja Specht, Dominik Böke, Irene Pazos, Anne-Sophie Rivier-Cordey, Damien P. Devos, Marko Kaksonen, Oriol Gallego
      The structural characterization of protein complexes in their native environment is challenging but crucial for understanding the mechanisms that mediate cellular processes. We developed an integrative approach to reconstruct the 3D architecture of protein complexes in vivo. We applied this approach to the exocyst, a hetero-octameric complex of unknown structure that is thought to tether secretory vesicles during exocytosis with a poorly understood mechanism. We engineered yeast cells to anchor the exocyst on defined landmarks and determined the position of its subunit termini at nanometer precision using fluorescence microscopy. We then integrated these positions with the structural properties of the subunits to reconstruct the exocyst together with a vesicle bound to it. The exocyst has an open hand conformation made of rod-shaped subunits that are interlaced in the core. The exocyst architecture explains how the complex can tether secretory vesicles, placing them in direct contact with the plasma membrane.
      Graphical abstract image Teaser Microscopy-derived spatial constraints allow modeling of the exocyst structure in vivo.

      PubDate: 2017-01-27T16:45:20Z
       
  • Cellular and Circuit Mechanisms Shaping the Perceptual Properties of the
           Primate Fovea
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Raunak Sinha, Mrinalini Hoon, Jacob Baudin, Haruhisa Okawa, Rachel O.L. Wong, Fred Rieke
      The fovea is a specialized region of the retina that dominates the visual perception of primates by providing high chromatic and spatial acuity. While the foveal and peripheral retina share a similar core circuit architecture, they exhibit profound functional differences whose mechanisms are unknown. Using intracellular recordings and structure-function analyses, we examined the cellular and synaptic underpinnings of the primate fovea. Compared to peripheral vision, the fovea displays decreased sensitivity to rapid variations in light inputs; this difference is reflected in the responses of ganglion cells, the output cells of the retina. Surprisingly, and unlike in the periphery, synaptic inhibition minimally shaped the responses of foveal midget ganglion cells. This difference in inhibition cannot however, explain the differences in the temporal sensitivity of foveal and peripheral midget ganglion cells. Instead, foveal cone photoreceptors themselves exhibited slower light responses than peripheral cones, unexpectedly linking cone signals to perceptual sensitivity.
      Graphical abstract image Teaser The unique perceptual features of the primate fovea are shaped by the properties of cone photoreceptors, rather than retinal circuit computations.

      PubDate: 2017-01-27T16:45:20Z
       
  • Interspecies Chimerism with Mammalian Pluripotent Stem Cells
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Jun Wu, Aida Platero-Luengo, Masahiro Sakurai, Atsushi Sugawara, Maria Antonia Gil, Takayoshi Yamauchi, Keiichiro Suzuki, Yanina Soledad Bogliotti, Cristina Cuello, Mariana Morales Valencia, Daiji Okumura, Jingping Luo, Marcela Vilariño, Inmaculada Parrilla, Delia Alba Soto, Cristina A. Martinez, Tomoaki Hishida, Sonia Sánchez-Bautista, M. Llanos Martinez-Martinez, Huili Wang, Alicia Nohalez, Emi Aizawa, Paloma Martinez-Redondo, Alejandro Ocampo, Pradeep Reddy, Jordi Roca, Elizabeth A. Maga, Concepcion Rodriguez Esteban, W. Travis Berggren, Estrella Nuñez Delicado, Jeronimo Lajara, Isabel Guillen, Pedro Guillen, Josep M. Campistol, Emilio A. Martinez, Pablo Juan Ross, Juan Carlos Izpisua Belmonte
      Interspecies blastocyst complementation enables organ-specific enrichment of xenogenic pluripotent stem cell (PSC) derivatives. Here, we establish a versatile blastocyst complementation platform based on CRISPR-Cas9-mediated zygote genome editing and show enrichment of rat PSC-derivatives in several tissues of gene-edited organogenesis-disabled mice. Besides gaining insights into species evolution, embryogenesis, and human disease, interspecies blastocyst complementation might allow human organ generation in animals whose organ size, anatomy, and physiology are closer to humans. To date, however, whether human PSCs (hPSCs) can contribute to chimera formation in non-rodent species remains unknown. We systematically evaluate the chimeric competency of several types of hPSCs using a more diversified clade of mammals, the ungulates. We find that naïve hPSCs robustly engraft in both pig and cattle pre-implantation blastocysts but show limited contribution to post-implantation pig embryos. Instead, an intermediate hPSC type exhibits higher degree of chimerism and is able to generate differentiated progenies in post-implantation pig embryos.
      Graphical abstract image Teaser Human pluripotent stem cells robustly engraft into both cattle and pig pre-implantation blastocysts, but show limited chimeric contribution to post-implantation pig embryos.

      PubDate: 2017-01-27T16:45:20Z
       
  • Pathogen-Mediated Inhibition of Anorexia Promotes Host Survival and
           Transmission
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Sheila Rao, Alexandria M. Palaferri Schieber, Carolyn P. O’Connor, Mathias Leblanc, Daniela Michel, Janelle S. Ayres
      Sickness-induced anorexia is a conserved behavior induced during infections. Here, we report that an intestinal pathogen, Salmonella Typhimurium, inhibits anorexia by manipulating the gut-brain axis. Inhibition of inflammasome activation by the S. Typhimurium effector, SlrP, prevented anorexia caused by IL-1β-mediated signaling to the hypothalamus via the vagus nerve. Rather than compromising host defenses, pathogen-mediated inhibition of anorexia increased host survival. SlrP-mediated inhibition of anorexia prevented invasion and systemic infection by wild-type S. Typhimurium, reducing virulence while increasing transmission to new hosts, suggesting that there are trade-offs between transmission and virulence. These results clarify the complex and contextual role of anorexia in host-pathogen interactions and suggest that microbes have evolved mechanisms to modulate sickness-induced behaviors to promote health of their host and their transmission at the expense of virulence.
      Graphical abstract image Teaser Pathogens can interfere with the gut-brain circuits that control host anorexia during infection to promote host survival while facilitating disease transmission.

      PubDate: 2017-01-27T16:45:20Z
       
  • Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in
           Metastatic Melanoma
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Willy Hugo, Jesse M. Zaretsky, Lu Sun, Chunying Song, Blanca Homet Moreno, Siwen Hu-Lieskovan, Beata Berent-Maoz, Jia Pang, Bartosz Chmielowski, Grace Cherry, Elizabeth Seja, Shirley Lomeli, Xiangju Kong, Mark C. Kelley, Jeffrey A. Sosman, Douglas B. Johnson, Antoni Ribas, Roger S. Lo


      PubDate: 2017-01-27T16:45:20Z
       
  • Zika Virus Causes Testis Damage and Leads to Male Infertility in Mice
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Wenqiang Ma, Shihua Li, Shuoqian Ma, Lina Jia, Fuchun Zhang, Yong Zhang, Jingyuan Zhang, Gary Wong, Shanshan Zhang, Xuancheng Lu, Mei Liu, Jinghua Yan, Wei Li, Chuan Qin, Daishu Han, Chengfeng Qin, Na Wang, Xiangdong Li, George Fu Gao


      PubDate: 2017-01-27T16:45:20Z
       
  • SnapShot: The Noncanonical Inflammasome
    • Abstract: Publication date: 26 January 2017
      Source:Cell, Volume 168, Issue 3
      Author(s): Jingjin Ding, Feng Shao
      This SnapShot depicts how the noncanonical inflammasome pathway is initiated and activated, as well as its effector mechanism in triggering pyroptosis and immune defenses.
      Teaser This SnapShot depicts how the noncanonical inflammasome pathway is initiated and activated, as well as its effector mechanism in triggering pyroptosis and immune defenses.

      PubDate: 2017-01-27T16:45:20Z
       
  • Ligand and Target Discovery by Fragment-Based Screening in Human Cells
    • Abstract: Publication date: Available online 19 January 2017
      Source:Cell
      Author(s): Christopher G. Parker, Andrea Galmozzi, Yujia Wang, Bruno E. Correia, Kenji Sasaki, Christopher M. Joslyn, Arthur S. Kim, Cullen L. Cavallaro, R. Michael Lawrence, Stephen R. Johnson, Iñigo Narvaiza, Enrique Saez, Benjamin F. Cravatt
      Advances in the synthesis and screening of small-molecule libraries have accelerated the discovery of chemical probes for studying biological processes. Still, only a small fraction of the human proteome has chemical ligands. Here, we describe a platform that marries fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible small molecule-protein interactions directly in human cells, many of which can be site-specifically determined. We show that fragment hits can be advanced to furnish selective ligands that affect the activity of proteins heretofore lacking chemical probes. We further combine fragment-based chemical proteomics with phenotypic screening to identify small molecules that promote adipocyte differentiation by engaging the poorly characterized membrane protein PGRMC2. Fragment-based screening in human cells thus provides an extensive proteome-wide map of protein ligandability and facilitates the coordinated discovery of bioactive small molecules and their molecular targets.
      Graphical abstract image Teaser A chemical proteomics platform enables the global mapping of reversible small-molecule fragment-protein interactions in cells.

      PubDate: 2017-01-20T22:06:11Z
       
  • ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and
           Aβ Secretion
    • Abstract: Publication date: Available online 19 January 2017
      Source:Cell
      Author(s): Yu-Wen Alvin Huang, Bo Zhou, Marius Wernig, Thomas C. Südhof
      Human apolipoprotein E (ApoE) apolipoprotein is primarily expressed in three isoforms (ApoE2, ApoE3, and ApoE4) that differ only by two residues. ApoE4 constitutes the most important genetic risk factor for Alzheimer’s disease (AD), ApoE3 is neutral, and ApoE2 is protective. How ApoE isoforms influence AD pathogenesis, however, remains unclear. Using ES-cell-derived human neurons, we show that ApoE secreted by glia stimulates neuronal Aβ production with an ApoE4 > ApoE3 > ApoE2 potency rank order. We demonstrate that ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases. Activated ERK1/2 induces cFos phosphorylation, stimulating the transcription factor AP-1, which in turn enhances transcription of amyloid-β precursor protein (APP) and thereby increases amyloid-β levels. This molecular mechanism also regulates APP transcription in mice in vivo. Our data describe a novel signal transduction pathway in neurons whereby ApoE activates a non-canonical MAP kinase cascade that enhances APP transcription and amyloid-β synthesis.
      Graphical abstract image Teaser A systematic investigation of how the three ApoE isoforms may contribute to Alzheimer’s disease pathogenesis reveals a direct role for ApoE in driving levels of APP and amyloid-β levels.

      PubDate: 2017-01-20T22:06:11Z
       
  • Structural Titration of Slo2.2, a Na+-Dependent K+ Channel
    • Abstract: Publication date: Available online 19 January 2017
      Source:Cell
      Author(s): Richard K. Hite, Roderick MacKinnon
      The stable structural conformations that occur along the complete reaction coordinate for ion channel opening have never been observed. In this study, we describe the equilibrium ensemble of structures of Slo2.2, a neuronal Na+-activated K+ channel, as a function of the Na+ concentration. We find that Slo2.2 exists in multiple closed conformations whose relative occupancies are independent of Na+ concentration. An open conformation emerges from an ensemble of closed conformations in a highly Na+-dependent manner, without evidence of Na+-dependent intermediates. In other words, channel opening is a highly concerted, switch-like process. The midpoint of the structural titration matches that of the functional titration. A maximum open conformation probability approaching 1.0 and maximum functional open probability approaching 0.7 imply that, within the class of open channels, there is a subclass that is not permeable to ions.
      Graphical abstract image Teaser Cryo-EM analyses of a protein ensemble under a range of conditions show that a neuronal Na+-activated K+ channel uses an all-or-nothing approach to opening.

      PubDate: 2017-01-20T22:06:11Z
       
  • Cooperative Binding of Transcription Factors Orchestrates Reprogramming
    • Abstract: Publication date: Available online 19 January 2017
      Source:Cell
      Author(s): Constantinos Chronis, Petko Fiziev, Bernadett Papp, Stefan Butz, Giancarlo Bonora, Shan Sabri, Jason Ernst, Kathrin Plath
      Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription factors (TFs), and chromatin states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that OSK predominantly bind active somatic enhancers early in reprogramming and immediately initiate their inactivation genome-wide by inducing the redistribution of somatic TFs away from somatic enhancers to sites elsewhere engaged by OSK, recruiting Hdac1, and repressing the somatic TF Fra1. Pluripotency enhancer selection is a stepwise process that also begins early in reprogramming through collaborative binding of OSK at sites with high OSK-motif density. Most pluripotency enhancers are selected later in the process and require OS and other pluripotency TFs. Somatic and pluripotency TFs modulate reprogramming efficiency when overexpressed by altering OSK targeting, somatic-enhancer inactivation, and pluripotency enhancer selection. Together, our data indicate that collaborative interactions among OSK and with stage-specific TFs direct both somatic-enhancer inactivation and pluripotency-enhancer selection to drive reprogramming.
      Graphical abstract image Teaser Oct4, Sox2, and Klf4 work collaboratively with the help of other transcription factors to change the enhancer landscape during reprogramming.

      PubDate: 2017-01-20T22:06:11Z
       
  • Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host
           Proteases
    • Abstract: Publication date: Available online 19 January 2017
      Source:Cell
      Author(s): Chun-Jun Guo, Fang-Yuan Chang, Thomas P. Wyche, Keriann M. Backus, Timothy M. Acker, Masanori Funabashi, Mao Taketani, Mohamed S. Donia, Stephen Nayfach, Katherine S. Pollard, Charles S. Craik, Benjamin F. Cravatt, Jon Clardy, Christopher A. Voigt, Michael A. Fischbach
      The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Escherichia coli or Bacillus subtilis, we show that they encode pyrazinones and dihydropyrazinones. At least one of the 47 clusters is present in 88% of the National Institutes of Health Human Microbiome Project (NIH HMP) stool samples, and they are transcribed under conditions of host colonization. We present evidence that the active form of these molecules is the initially released peptide aldehyde, which bears potent protease inhibitory activity and selectively targets a subset of cathepsins in human cell proteomes. Our findings show that an approach combining bioinformatics, synthetic biology, and heterologous gene cluster expression can rapidly expand our knowledge of the metabolic potential of the microbiota while avoiding the challenges of cultivating fastidious commensals.
      Graphical abstract image Teaser Guo et al. report the discovery of a new family of microbial metabolites that are widely produced by the microbes of the human gut and that chemically modify host cellular proteins.

      PubDate: 2017-01-20T22:06:11Z
       
  • Systemic Immunity Is Required for Effective Cancer Immunotherapy
    • Abstract: Publication date: Available online 19 January 2017
      Source:Cell
      Author(s): Matthew H. Spitzer, Yaron Carmi, Nathan E. Reticker-Flynn, Serena S. Kwek, Deepthi Madhireddy, Maria M. Martins, Pier Federico Gherardini, Tyler R. Prestwood, Jonathan Chabon, Sean C. Bendall, Lawrence Fong, Garry P. Nolan, Edgar G. Engleman
      Immune responses involve coordination across cell types and tissues. However, studies in cancer immunotherapy have focused heavily on local immune responses in the tumor microenvironment. To investigate immune activity more broadly, we performed an organism-wide study in genetically engineered cancer models using mass cytometry. We analyzed immune responses in several tissues after immunotherapy by developing intuitive models for visualizing single-cell data with statistical inference. Immune activation was evident in the tumor and systemically shortly after effective therapy was administered. However, during tumor rejection, only peripheral immune cells sustained their proliferation. This systemic response was coordinated across tissues and required for tumor eradication in several immunotherapy models. An emergent population of peripheral CD4 T cells conferred protection against new tumors and was significantly expanded in patients responding to immunotherapy. These studies demonstrate the critical impact of systemic immune responses that drive tumor rejection.
      Graphical abstract image Teaser A systems approach reveals that engagement of systemic immunity is critical to the process of tumor rejection following immunotherapy.

      PubDate: 2017-01-20T22:06:11Z
       
  • Redefining Biology via Enzyme Engineering
    • Abstract: Publication date: 12 January 2017
      Source:Cell, Volume 168, Issues 1–2
      Author(s): Mirna Kvajo


      PubDate: 2017-01-13T14:47:36Z
       
  • In Search of Scientific Inspiration
    • Abstract: Publication date: 12 January 2017
      Source:Cell, Volume 168, Issues 1–2
      In the ever-expanding sea of scientific advances, how do you find inspiration for your own study? Cell editor Jiaying Tan talked with Mark Lemmon and Joseph (Yossi) Schlessinger about the importance of fueling your research creativity with the conceptual excitement and technical advance from the broad scientific field. An excerpt of the conversation appears below.
      Teaser In the ever-expanding sea of scientific advances, how do you find inspiration for your own study? Cell editor Jiaying Tan talked with Mark Lemmon and Joseph (Yossi) Schlessinger about the importance of fueling your research creativity with the conceptual excitement and technical advance from the broad scientific field. An excerpt of the conversation appears below.

      PubDate: 2017-01-13T14:47:36Z
       
  • GABA Signaling Stimulates β Cell Regeneration in Diabetic Mice
    • Abstract: Publication date: 12 January 2017
      Source:Cell, Volume 168, Issues 1–2
      Author(s): Gordon C. Weir, Susan Bonner-Weir
      GABA and the antimalarial drug artemether, which acts on GABAergic pathways, can drive pancreatic cells with an α-cell phenotype toward a β-cell-like phenotype. As reported in two papers (Ben-Othman et al. and Li et al.), these drugs can stimulate the production of sufficient numbers of new β-like cells to reverse severe diabetes in mice.
      Teaser GABA and the antimalarial drug artemether, which acts on GABAergic pathways, can drive pancreatic cells with an α-cell phenotype toward a β-cell-like phenotype. As reported in two papers (Ben-Othman et al. and Li et al.), these drugs can stimulate the production of sufficient numbers of new β-like cells to reverse severe diabetes in mice.

      PubDate: 2017-01-13T14:47:36Z
       
  • The Interfaces of Genetic Conflict Are Hot Spots for Innovation
    • Abstract: Publication date: 12 January 2017
      Source:Cell, Volume 168, Issues 1–2
      Author(s): Joshua Carter, Connor Hoffman, Blake Wiedenheft
      RNA-guided Cas9 endonucleases protect bacteria from viral infection and have been creatively repurposed as programmable molecular scalpels for surgical manipulation of DNA. Now, two papers in Cell (Pawluk et al. and Rauch et al.) identify viral proteins that suppress Cas9 and may function like molecular sheaths for the Cas9 scalpel.
      Teaser RNA-guided Cas9 endonucleases protect bacteria from viral infection and have been creatively repurposed as programmable molecular scalpels for surgical manipulation of DNA. Now, two papers in Cell (Pawluk et al. and Rauch et al.) identify viral proteins that suppress Cas9 and may function like molecular sheaths for the Cas9 scalpel.

      PubDate: 2017-01-13T14:47:36Z
       
  • Shining a Light on Phase Separation in the Cell
    • Abstract: Publication date: 12 January 2017
      Source:Cell, Volume 168, Issues 1–2
      Author(s): Giulia Paci, Edward A. Lemke
      Phase separation of proteins is recognized as an important aspect of cellular organization and disease mechanisms. Shin et al. introduce a novel optogenetic tool, which enables different phase-space regimes inside living cells to be assessed and the transition paths between them to be studied with unprecedented spatiotemporal control.
      Teaser Phase separation of proteins is recognized as an important aspect of cellular organization and disease mechanisms. Shin et al. introduce a novel optogenetic tool, which enables different phase-space regimes inside living cells to be assessed and the transition paths between them to be studied with unprecedented spatiotemporal control.

      PubDate: 2017-01-13T14:47:36Z
       
  • Insertions and Deletions Target Lineage-Defining Genes in Human Cancers
    • Abstract: Publication date: Available online 12 January 2017
      Source:Cell
      Author(s): Marcin Imielinski, Guangwu Guo, Matthew Meyerson
      Certain cell types function as factories, secreting large quantities of one or more proteins that are central to the physiology of the respective organ. Examples include surfactant proteins in lung alveoli, albumin in liver parenchyma, and lipase in the stomach lining. Whole-genome sequencing analysis of lung adenocarcinomas revealed noncoding somatic mutational hotspots near VMP1/MIR21 and indel hotspots in surfactant protein genes (SFTPA1, SFTPB, and SFTPC). Extrapolation to other solid cancers demonstrated highly recurrent and tumor-type-specific indel hotspots targeting the noncoding regions of highly expressed genes defining certain secretory cellular lineages: albumin (ALB) in liver carcinoma, gastric lipase (LIPF) in stomach carcinoma, and thyroglobulin (TG) in thyroid carcinoma. The sequence contexts of indels targeting lineage-defining genes were significantly enriched in the AATAATD DNA motif and specific chromatin contexts, including H3K27ac and H3K36me3. Our findings illuminate a prevalent and hitherto unrecognized mutational process linking cellular lineage and cancer.
      Graphical abstract image Teaser Certain highly expressed, lineage-defining genes are targeted by a novel somatic mutational process.

      PubDate: 2017-01-13T14:47:36Z
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
Home (Search)
Subjects A-Z
Publishers A-Z
Customise
APIs
Your IP address: 54.158.174.84
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2016