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Cell Metabolism
This journal offers authors two options (open access or subscription) to publish research

Dec 04, 2018

Volume 28Issue 6p801-962
Open Archive
On the cover: Cancer combination therapy, whereby more than one type of treatment modality is used to combat the disease, is becoming a mainstay in the fight against cancer. In this issue of Cell Metabolism, Hulea et al. (pp. 817–832) and Kurmi et al. (pp. 833–847) target cancer metabolic vulnerabilities through combination therapy using the diabetes drug metformin with kinase inhibitors and through the combination of cyclocreatine and the HER2 kinase inhibitor lapatinib, respectively. The cover image captures the concept of unlocking combination therapies, including repurposing old drugs, to charter new horizons for precision cancer metabolic therapy. Cover design by Rosalind Mott; images credit: iStock/teekid, iStock/Golgaz, iStock/Ideas_studio....
On the cover: Cancer combination therapy, whereby more than one type of treatment modality is used to combat the disease, is becoming a mainstay in the fight against cancer. In this issue of Cell Metabolism, Hulea et al. (pp. 817–832) and Kurmi et al. (pp. 833–847) target cancer metabolic vulnerabilities through combination therapy using the diabetes drug metformin with kinase inhibitors and through the combination of cyclocreatine and the HER2 kinase inhibitor lapatinib, respectively. The cover image captures the concept of unlocking combination therapies, including repurposing old drugs, to charter new horizons for precision cancer metabolic therapy. Cover design by Rosalind Mott; images credit: iStock/teekid, iStock/Golgaz, iStock/Ideas_studio.

Previews

  • Peeking under the Hood of Naive T Cells

    • Wei Xu,
    • Jonathan D. Powell
    Signaling and transcriptional regulation of metabolic reprogramming upon T cell activation has been studied intensively. In this issue of Cell Metabolism, Ricciardi et al. (2018) show that translational regulation of key metabolic enzymes GLUT1 and ACC1 plays a novel role in human naive CD4 T cell activation and subset differentiation.
  • Cancer-Induced Endoplasmic Reticulum Stress in T Cells Subverts Immunosurveillance

    • Alejandro López-Soto,
    • Guido Kroemer
    Compelling evidence indicates that tumors may evade immunosurveillance by subverting the metabolism of immune cells. In a recent paper in Nature, Song et al. (2018) demonstrate that ovarian cancers activate IRE1α-XBP1 signaling within CD4+ T lymphocytes, thereby disrupting their bioenergetic function and contribution to anticancer immune responses.
  • HER2 Signaling Hijacks the Creatine Shuttle to Fuel Breast Cancer Cell Growth

    • Issam Ben-Sahra,
    • Alexandre Puissant
    Alteration of cell energy metabolism represents a major determinant of cancer progression; however, our understanding of oncogenic mechanisms underlying this rewiring remains elusive. In this issue of Cell Metabolism, Kurmi et al. (2018) show that HER2 signaling promotes ABL-mediated phosphorylation of the mitochondrial creatine kinase (MtCK1), providing ATP to support breast tumor growth.
  • A Gut Feeling for Metformin

    • David Z.I. Cherney,
    • Tony K.T. Lam
    Metformin is a first-line glucose-lowering agent in patients with type 2 diabetes (T2D). Recently in Nature Medicine, Sun et al. (2018) reported that short-term metformin therapy decreases gut Bacteroides fragilis, consequently increasing glycoursodexoycholic acid (GUDCA) levels in humans. As an antagonist of FXR, GUDCA may carry therapeutic potential in the treatment of T2D.
  • Parasitic Behavior of Leukemic Cells in Systemic Host Metabolism

    • Julie Leca,
    • Thorsten Berger,
    • Tak Wah Mak
    Metabolic reprogramming is a hallmark of cancer cell metabolism. Recently, in Cancer Cell, Ye and colleagues (2018) reported that leukemic cells have the capacity to modulate glucose metabolism in multiple organs of their host, thereby increasing the glucose resources available for malignant cell growth.
  • Can We DECLARE a Victory against Cardio-Renal Disease in Diabetes?

    • Kim A. Connelly,
    • Deepak L. Bhatt,
    • Subodh Verma
    Heart failure and renal disease remain significant complications in people with type 2 diabetes (T2D). Recent outcome studies with sodium-glucose cotransporter-2 (SGLT2) inhibitors have provided increasing insights, with the latest reporting trial DECLARE-TIMI 58 (Wiviott et al., 2018), pointing toward a role for these agents in the primary prevention of cardio-renal complications in T2D.

Articles

  • Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides

    • Laura Hulea,
    • Simon-Pierre Gravel,
    • Masahiro Morita,
    • Marie Cargnello,
    • Oro Uchenunu,
    • Young Kyuen Im,
    • Camille Lehuédé,
    • Eric H. Ma,
    • Matthew Leibovitch,
    • Shannon McLaughlan,
    • Marie-José Blouin,
    • Maxime Parisotto,
    • Vasilios Papavasiliou,
    • Cynthia Lavoie,
    • Ola Larsson,
    • Michael Ohh,
    • Tiago Ferreira,
    • Celia Greenwood,
    • Gaëlle Bridon,
    • Daina Avizonis,
    • Gerardo Ferbeyre,
    • Peter Siegel,
    • Russell G. Jones,
    • William Muller,
    • Josie Ursini-Siegel,
    • Julie St-Pierre,
    • Michael Pollak,
    • Ivan Topisirovic
    Hulea et al. investigate the mechanisms underlying the synergic efficacy of kinase inhibitors (KIs) and biguanides in targeting cancer cells and show that different pathways involving mTORC1, 4E-BP, and HIF-1α are at play. Cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms, which allows them to survive therapy combinations.
  • Tyrosine Phosphorylation of Mitochondrial Creatine Kinase 1 Enhances a Druggable Tumor Energy Shuttle Pathway

    • Kiran Kurmi,
    • Sadae Hitosugi,
    • Jia Yu,
    • Felix Boakye-Agyeman,
    • Elizabeth K. Wiese,
    • Thomas R. Larson,
    • Qing Dai,
    • Yuichi J. Machida,
    • Zhenkun Lou,
    • Liewei Wang,
    • Judy C. Boughey,
    • Scott H. Kaufmann,
    • Matthew P. Goetz,
    • Larry M. Karnitz,
    • Taro Hitosugi
    Kurmi et al. report that the phosphocreatine (PCr) energy shuttle is important for breast tumor metabolism and growth. This energy shuttle is activated through MtCK1 Y153 phosphorylation by the HER2/ABL signaling axis. Using a creatine analog cyclocreatine that inhibits the PCr energy shuttle, they demonstrate reduced growth of trastuzumab-resistant breast tumors in mice.
  • Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies

    • Maria Apicella,
    • Elisa Giannoni,
    • Stephany Fiore,
    • Karin Johanna Ferrari,
    • Daniel Fernández-Pérez,
    • Claudio Isella,
    • Carlotta Granchi,
    • Filippo Minutolo,
    • Antonino Sottile,
    • Paolo Maria Comoglio,
    • Enzo Medico,
    • Filippo Pietrantonio,
    • Marco Volante,
    • Diego Pasini,
    • Paola Chiarugi,
    • Silvia Giordano,
    • Simona Corso
    The tumor microenvironment shapes cancer progression. Apicella et al. now show that cancer-associated fibroblasts play an active metabolic role in adaptive cancer drug resistance to tyrosine kinase inhibitors (TKIs). Targeting the non-cell-autonomous lactate/HGF/MET-signaling axis abrogated acquired TKI resistance in cancer models.
  • Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation

    • Ulrike Bruning,
    • Francisco Morales-Rodriguez,
    • Joanna Kalucka,
    • Jermaine Goveia,
    • Federico Taverna,
    • Karla C.S. Queiroz,
    • Charlotte Dubois,
    • Anna Rita Cantelmo,
    • Rongyuan Chen,
    • Stefan Loroch,
    • Evy Timmerman,
    • Vanessa Caixeta,
    • Katarzyna Bloch,
    • Lena-Christin Conradi,
    • Lucas Treps,
    • An Staes,
    • Kris Gevaert,
    • Andrew Tee,
    • Mieke Dewerchin,
    • Clay F. Semenkovich,
    • Francis Impens,
    • Birgit Schilling,
    • Eric Verdin,
    • Johannes V. Swinnen,
    • Jordan L. Meier,
    • Rhushikesh A. Kulkarni,
    • Albert Sickmann,
    • Bart Ghesquière,
    • Luc Schoonjans,
    • Xuri Li,
    • Massimiliano Mazzone,
    • Peter Carmeliet
    Bruning et al. report that blocking fatty acid synthase (FASN) in endothelial cells (ECs) reduces angiogenesis by impairing EC proliferation. Mechanistically, FASN inhibition elevates the malonyl-CoA substrate pool, thereby increasing post-translational malonylation of mTOR and decreasing the pro-angiogenic mTORC1 activity.
  • Quiescent Endothelial Cells Upregulate Fatty Acid β-Oxidation for Vasculoprotection via Redox Homeostasis

    • Joanna Kalucka,
    • Laura Bierhansl,
    • Nadine Vasconcelos Conchinha,
    • Rindert Missiaen,
    • Ilaria Elia,
    • Ulrike Brüning,
    • Samantha Scheinok,
    • Lucas Treps,
    • Anna Rita Cantelmo,
    • Charlotte Dubois,
    • Pauline de Zeeuw,
    • Jermaine Goveia,
    • Annalisa Zecchin,
    • Federico Taverna,
    • Francisco Morales-Rodriguez,
    • Aleksandra Brajic,
    • Lena-Christin Conradi,
    • Sandra Schoors,
    • Ulrike Harjes,
    • Kim Vriens,
    • Gregor-Alexander Pilz,
    • Rongyuan Chen,
    • Richard Cubbon,
    • Bernard Thienpont,
    • Bert Cruys,
    • Brian W. Wong,
    • Bart Ghesquière,
    • Mieke Dewerchin,
    • Katrien De Bock,
    • Xavier Sagaert,
    • Sebastian Jessberger,
    • Elizabeth A.V. Jones,
    • Bernard Gallez,
    • Diether Lambrechts,
    • Massimiliano Mazzone,
    • Guy Eelen,
    • Xuri Li,
    • Sarah-Maria Fendt,
    • Peter Carmeliet
    Kalucka et al. show that fatty acid β-oxidation in quiescent endothelial cells (QECs) is indispensable to maintain redox balance and prevent EC dysfunction. In contrast to proliferating ECs (PECs), QECs reprogram their metabolism to increase regeneration of NAPDH, which is then used by vasculoprotective (NADPH-consuming) enzymes for redox homeostasis.
  • The Translational Machinery of Human CD4+ T Cells Is Poised for Activation and Controls the Switch from Quiescence to Metabolic Remodeling

    • Sara Ricciardi,
    • Nicola Manfrini,
    • Roberta Alfieri,
    • Piera Calamita,
    • Maria Cristina Crosti,
    • Simone Gallo,
    • Rolf Müller,
    • Massimiliano Pagani,
    • Sergio Abrignani,
    • Stefano Biffo
    Ricciardi et al. show that the translation of pre-accumulated mRNAs encoding key players in glycolytic and fatty acid synthesis drives metabolic reprogramming of naive T cells. Upon TCR activation, the poised translational machinery is activated, thereby coordinating the translation of GLUT1 and ACC1 mRNAs and linking metabolism to effector cell fate.
  • Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements

    • Salvatore Fabbiano,
    • Nicolas Suárez-Zamorano,
    • Claire Chevalier,
    • Vladimir Lazarević,
    • Silas Kieser,
    • Dorothée Rigo,
    • Stefano Leo,
    • Christelle Veyrat-Durebex,
    • Nadia Gaïa,
    • Marcello Maresca,
    • Doron Merkler,
    • Mercedes Gomez de Agüero,
    • Andrew Macpherson,
    • Jacques Schrenzel,
    • Mirko Trajkovski
    Fabbiano et al. show that gut microbiota remodeling is important for the metabolic improvements associated with caloric restriction, including fat browning and improved glycemic control. They link the systemic beneficial metabolic effects to reduced endotoxin production, leading to increased type 2 immune response in the adipose tissue.
  • Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection

    • Sue Tsai,
    • Xavier Clemente-Casares,
    • Angela C. Zhou,
    • Helena Lei,
    • Jennifer J. Ahn,
    • Yi Tao Chan,
    • Okmi Choi,
    • Helen Luck,
    • Minna Woo,
    • Shannon E. Dunn,
    • Edgar G. Engleman,
    • Tania H. Watts,
    • Shawn Winer,
    • Daniel A. Winer
    Tsai et al. report that insulin signaling plays an important role in tuning the immune response. Specifically, insulin receptor signaling has an impact on T cell glucose metabolism and amino acid handling. In mouse models, insulin receptor-deficient T cells exhibit reduced inflammatory potential and poor protective immunity against H1N1 influenza infection.

Short Article

Resource

  • Conventional and Neo-antigenic Peptides Presented by β Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors

    • Sergio Gonzalez-Duque,
    • Marie Eliane Azoury,
    • Maikel L. Colli,
    • Georgia Afonso,
    • Jean-Valery Turatsinze,
    • Laura Nigi,
    • Ana Ines Lalanne,
    • Guido Sebastiani,
    • Alexia Carré,
    • Sheena Pinto,
    • Slobodan Culina,
    • Noémie Corcos,
    • Marco Bugliani,
    • Piero Marchetti,
    • Mathieu Armanet,
    • Marc Diedisheim,
    • Bruno Kyewski,
    • Lars M. Steinmetz,
    • Søren Buus,
    • Sylvaine You,
    • Daniele Dubois-Laforgue,
    • Etienne Larger,
    • Jean-Paul Beressi,
    • Graziella Bruno,
    • Francesco Dotta,
    • Raphael Scharfmann,
    • Decio L. Eizirik,
    • Yann Verdier,
    • Joelle Vinh,
    • Roberto Mallone
    Mallone et al. use peptidomics and transcriptomics to identify the epitopes presented by β cells that trigger type 1 diabetes (T1D) autoimmunity. Multiple pathways, including conventional processing and mRNA and peptide splicing, are involved in epitope generation and presentation; these epitopes are selectively recognized by pancreas-infiltrating CD8+ T lymphocytes in T1D patients.

Correction

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