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  • MED13‐dependent signaling from the heart confers leanness by enhancing metabolism in adipose tissue and liver
    1. Kedryn K Baskin1,,
    2. Chad E Grueter2,,
    3. Christine M Kusminski3,
    4. William L Holland3,
    5. Angie L Bookout1,
    6. Santosh Satapati4,5,
    7. Y Megan Kong1,
    8. Shawn C Burgess4,5,
    9. Craig R Malloy4,5,6,7,
    10. Philipp E Scherer3,8,
    11. Christopher B Newgard9,10,11,
    12. Rhonda Bassel‐Duby1,12 and
    13. Eric N Olson*,1,12
    1. 1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. 2Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
    3. 3Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
    4. 4Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
    5. 5Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    6. 6Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    7. 7Department of Molecular Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA
    8. 8Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    9. 9Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC, USA
    10. 10Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
    11. 11Department of Pharmacology and Cancer Biology, Department of Medicine, Duke University, Durham, NC, USA
    12. 12Hamon Center for Regenerative Science and Medicine, Dallas, TX, USA
    1. *Corresponding author. Tel: +1 214 648 1187; Fax: +1 214 648 1196; E‐mail: eric.olson{at}utsouthwestern.edu
    1. These authors contributed equally to this work

    Cardiac MED13 enhances the use by the heart and the body of fuel resources available after or between meals. The heart thereby regulates systemic energy expenditure via circulating factors to promote enhanced metabolism and leanness.

    Synopsis

    Cardiac MED13 enhances the use by the heart and the body of fuel resources available after or between meals. The heart thereby regulates systemic energy expenditure via circulating factors to promote enhanced metabolism and leanness.

    • Cardiac overexpression of MED13 increases lipid metabolism in adipose tissue and liver.

    • Enhanced metabolism in MED13cTg mice is not pathological, as MED13cTg mice metabolically adapt to fasting.

    • Leanness is regulated by circulating factors in MED13cTg mice.

    • Metabolic rates of wild‐type mice are increased by systemic delivery of “lean factors”.

    • energy homeostasis
    • mediator complex
    • metabolic flexibility
    • metabolic gene expression
    • metabolism
    • Received May 1, 2014.
    • Revision received October 22, 2014.
    • Accepted October 23, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Kedryn K Baskin, Chad E Grueter, Christine M Kusminski, William L Holland, Angie L Bookout, Santosh Satapati, Y Megan Kong, Shawn C Burgess, Craig R Malloy, Philipp E Scherer, Christopher B Newgard, Rhonda Bassel‐Duby, Eric N Olson
  • Key drivers of biomedical innovation in cancer drug discovery
    1. Margit A Huber*,1 and
    2. Norbert Kraut*,2
    1. 1Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
    2. 2Oncology Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
    1. * Corresponding author. Tel: +49 731 500 57647; E‐mail: margit.huber{at}uniklinik-ulm.de

      Corresponding author. E‐mail: norbert.kraut{at}boehringer-ingelheim.com

    Discovery and translational research has led to the identification of a series of “cancer drivers”—genes that, when mutated or otherwise misregulated, can drive malignancy. An increasing number of drugs that directly target such drivers have demonstrated activity in clinical trials and are shaping a new landscape for molecularly targeted cancer therapies. Such therapies rely on molecular and genetic diagnostic tests to detect the presence of a biomarker that predicts response. Here, we highlight some of the key discoveries bringing precision oncology to cancer patients. Large‐scale “omics” approaches as well as modern, hypothesis‐driven science in both academic and industry settings have significantly contributed to the field. Based on these insights, we discuss current challenges and how to foster future biomedical innovation in cancer drug discovery and development.

    Huber and Kraut discuss the current challenges in drug discovery including drug resistance and the need for improved preclinical models, and how to accelerate biomedical innovation through enhanced collaboration between academia and industry.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Margit A Huber, Norbert Kraut
  • Biology, detection, and clinical implications of circulating tumor cells
    1. Simon A Joosse1,,
    2. Tobias M Gorges1, and
    3. Klaus Pantel*,1
    1. 1Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany
    1. *Corresponding author. Tel: +49 40 7410 53503; E‐mail: pantel{at}uke.de
    1. Contributed equally.

    An overview of the biology of tumor cell dissemination, including an in depth discussion of the current advances and limitations in the detection/isolation of circulating tumor cells and their potential prognostic and diagnostic value.

    • Disseminating tumor cells (DTC)
    • EMT
    • metastasis
    • tumor cell dormancy
    • tumor cell plasticity
    • Received July 15, 2014.
    • Revision received October 2, 2014.
    • Accepted October 20, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Simon A Joosse, Tobias M Gorges, Klaus Pantel
  • Assessing metastasis risk after pre‐operative anti‐angiogenic therapy
    1. Daniela Biziato1 and
    2. Michele De Palma (michele.depalma{at}epfl.ch) 1
    1. 1The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Anti‐angiogenic drugs are approved for the treatment of several cancer types, generally in the inoperable locally advanced or metastatic setting and in combination with other anti‐cancer agents. Recent clinical studies also suggest that anti‐angiogenic drugs can be useful in the pre‐operative (neoadjuvant) setting, by facilitating the shrinkage of the primary tumour and its surgical resection. However, the effects of neoadjuvant anti‐angiogenic therapy on the ability of tumours to form distant metastases are unclear. In this issue of EMBO Molecular Medicine, Ebos et al (2014) present carefully performed pre‐clinical studies in mice that analyse the effects of pre‐operative anti‐angiogenic therapy on tumour metastasis and survival.

    See also: JML Ebos et al

    Biziato and De Palma comment on a mouse pre‐clinical study from Ebos, Kerbel et al suggesting that low‐dose metronomic chemotherapy may be combined with multi‐kinase angiogenesis inhibitors in a neoadjuvant setting to improve efficacy and safety.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Daniela Biziato, Michele De Palma
  • Deletion of the von Hippel–Lindau gene causes sympathoadrenal cell death and impairs chemoreceptor‐mediated adaptation to hypoxia
    1. David Macías1,2,3,
    2. Mary Carmen Fernández‐Agüera1,2,3,
    3. Victoria Bonilla‐Henao1,2,3 and
    4. José López‐Barneo*,1,2,3
    1. 1Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
    2. 2Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
    3. 3Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
    1. *Corresponding author. Tel: +34 955 923007; E‐mail: lbarneo{at}us.es

    Instead of tumorigenesis, Vhl inactivation in rodent catecholaminergic cells in vivo causes atrophy of the adrenal medulla, carotid body (CB) and sympathetic ganglia. Hypoxia‐induced adult CB neurogenesis is inhibited and Vhl‐KO mice cannot acclimatize to hypoxia.

    Synopsis

    Instead of tumorigenesis, Vhl inactivation in rodent catecholaminergic cells in vivo causes atrophy of the adrenal medulla, carotid body (CB) and sympathetic ganglia. Hypoxia‐induced adult CB neurogenesis is inhibited and Vhl‐KO mice cannot acclimatize to hypoxia.

    • Contrary to generally held beliefs Vhl is not a tumor suppressor gene in all cells.

    • Vhl‐deficiency in mouse sympathoadrenal cells does not result in the appearance of tumors.

    • Pheochromocytomas in man could be associated with gain‐of‐function mutations in VHL.

    • Animals lacking Vhl exhibit atrophy of the CB and adrenal medulla and present a striking intolerance to systemic hypoxia that could give rise to death.

    • adult carotid body neurogenesis
    • intolerance to hypoxia
    • sympathoadrenal tumorigenesis
    • Vhl‐deficient mouse model
    • von Hippel–Lindau protein
    • Received April 8, 2014.
    • Revision received October 15, 2014.
    • Accepted October 20, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    David Macías, Mary Carmen Fernández‐Agüera, Victoria Bonilla‐Henao, José López‐Barneo
  • Suppressing nonsense—a surprising function for 5‐azacytidine
    1. Ada Shao1 and
    2. Miles F Wilkinson (mfwilkinson{at}ucsd.edu) 1
    1. 1Department of Reproductive Medicine, University of California, San Diego, CA, USA

    In this issue of EMBO Molecular Medicine, Bhuvanagiri et al report on a chemical means to convert molecular junk into gold. They identify a chemical inhibitor of a quality control pathway that is best known for its ability to clear cells of rubbish, but that in certain cases can be detrimental because it eliminates “useful” garbage. The chemical inhibitor identified by Bhuvanagiri et al perturbs Nonsense‐Mediated RNA Decay (NMD), a RNA surveillance pathway that targets mRNAs harboring premature termination codons (PTCs) for degradation (Kervestin & Jacobson, 2012).

    See also: M Bhuvanagiri et al

    Shao & Wilkinson comment on the finding by the Kulozik and Hentze laboratories that FDA‐approved 5AzaC is a NMD inhibitor that could be potentially repurposed for the treatment of NMD‐induced diseases.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Ada Shao, Miles F Wilkinson
  • Tipping the MYC–MIZ1 balance: targeting the HUWE1 ubiquitin ligase selectively blocks MYC‐activated genes
    1. Franz X Schaub1 and
    2. John L Cleveland (John.Cleveland{at}moffitt.org) 1
    1. 1Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    MYC family oncoproteins (MYC, N‐MYC and L‐MYC) function as basic helix‐loop‐helix‐leucine zipper (bHLH‐Zip) transcription factors that are activated (i.e., overexpressed) in well over half of all human malignancies (Boxer & Dang, 2001; Beroukhim et al, 2010). In this issue of EMBO Molecular Medicine, Eilers and colleagues (Peter et al, 2014) describe a novel approach to disable MYC, whereby inhibition of the ubiquitin ligase HUWE1 stabilizes MIZ1 and leads to the selective repression of MYC‐activated target genes.

    See also: S Peter et al

    Schaub and Cleveland comment on the finding by Peter, Eilers et al that MYC can be selectively targeted in cancer by disabling the HUWE1 ubiquitin ligase that normally controls MIZ1 protein levels.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Franz X Schaub, John L Cleveland