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RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy

NATURE 2021年第7842期589卷 442-+页

作者： Paolino, Magdalena Koglgruber, Rubina Cronin, Shane J. F. uribesalgo, iris Rauscher, Esther Harreiter, Juergen Schuster, Michael Bancher-Todesca, Dagmar Pranjic, Blanka Novatchkova, Maria Fededa, Juan P. White, Andrea J. Sigl, Verena Dekan, Sabine Penz, Thomas Bock, Christoph Kenner, Lukas Hollander, Georg A. Anderson, Graham Kautzky-Willer, Alexandra Penninger, Josef M. Austrian Acad Sci IMBA Inst Mol Biotechnol Vienna Austria Karolinska Inst Dept Med Solna Stockholm Sweden Karolinska Univ Hosp Stockholm Sweden Med Univ Vienna Div Endocrinol & Metab Dept Med 3 Gender Med Unit Vienna Austria Austrian Acad Sci CeMM Res Ctr Mol Med Vienna Austria Med Univ Vienna Div Obstet & Fetomaternal Med Dept Obstet & Gynecol Vienna Austria Univ Nacl San Martin Inst Invest Biotecnol Dr Rodolfo A Ugalde IIB UNSAM IIBIO CONICET Buenos Aires DF Argentina Univ Birmingham Inst Immunol & Immunotherapy Inst Biomed Res Med Sch Birmingham W Midlands England Med Univ Vienna Dept Pathol Vienna Austria Med Univ Vienna Dept Lab Med Vienna Austria Med Univ Vienna Div Expt & Translat Pathol Dept Pathol Vienna Austria Ctr Biomarker Res Med CBmed Graz Austria Univ Vet Med Vienna Unit Lab Anim Pathol Vienna Austria Med Univ Vienna Christian Doppler Lab Appl Metabol CDL Vienna Austria Univ Basel Dept Biomed Paediat Immunol Basel Switzerland Univ Childrens Hosp Basel Basel Switzerland Univ Oxford Dept Paediat Oxford England Univ Oxford Weatherall Inst Mol Med Oxford England Swiss Fed Inst Technol Dept Biosyst Sci & Engn Basel Switzerland Austrian Inst Gender Med Gars Austria Univ British Columbia Life Sci Inst Dept Med Genet Vancouver BC Canada

Successful pregnancies rely on adaptations within the mother(1), including marked changes within the immune system(2). It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy(3). However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK(4,5) couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T-reg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T-reg cells through RANK in a manner that depends on AIRE(+) medullary thymic epithelial cells. The depletion of Rankin the mouse thymic epithelium results in reduced accumulation of natural T-reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T-reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T-reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T-reg cells during pregnancy, and expand the functional role of maternal T-reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.

关键词： Gestational diabetes Thymus

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AIF-regulated oxidative phosphorylation supports lung cancer development

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细胞研究（英文版） 2019年第7期29卷 579-591页

作者： Shuan Rao Laura Mondragón Blanka Pranjic Toshikatsu Hanada Gautier Stoll Thomas K(o)cher Peng Zhang Alexander Jais Alexander Lercher Andreas Bergthaler Daniel Schramek Katharina Haigh Valentina Sica Marion Leduc Nazanine Modjtahedi Tsung-Pin Pai Masahiro Onji iris uribesalgo Reiko Hanada Ivona Kozieradzki Rubina Koglgruber Shane J.Cronin Zhigang She Franz Quehenberger Helmut Popper Lukas Kenner Jody J.Haigh Oliver Kepp Malgorzata Rak Kaican Cai Guido Kroemer Josef M.Penninger Department of Thoracic Surgery Nanfang Hospital Southern Medical University Guangzhou Guangdong China IMBA Institute of Molecular Biotechnology of the Austrian Academy of Sciences 1030 Vienna Austria Equipe 11 labellisée Ligue contre le Cancer Centre de Recherche des Cordeliers 75006 Paris France INSERM U1138 75006 ParisFrance Université Paris Descartes Sorbonne Paris Cité Paris France Metabolomics and Cell Biology Platforms Gustave Roussy Cancer Campus 94805 Villejuif France IMBA Institute of Molecular Biotechnology of the Austrian Academy of Sciences 1030 Vienna Austria Equipe 11 labellisée Ligue contre le Cancer Centre de Recherche des Cordeliers 75006 Paris France INSERM U1138 75006 ParisFrance Université Paris Descartes Sorbonne Paris Cité Paris France Metabolomics and Cell Biology Platforms Gustave Roussy Cancer Campus 94805 Villejuif France Université Sorbonne 75006 Paris France Vienna Biocenter Core Facilities 1030 Vienna Austria Medical Science Research Center Zhongnan Hospital of Wuhan UniversityWuhan Hubei China Department of Neuronal Control of Metabolism Max Planck Institute for Metabolism Research Cologne Germany Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria Lunenfeld-Tanenbaum Research Institute Mount Sinai Hospital 600 University Avenue Toronto Canada Vascular Cell Biology Unit Department for Molecular Biomedical Research VIB Ghent Belgium Department of Biomedical Molecular Biology Ghent University GhentBelgium Department of Pharmacology and Therapeutics Rady Faculty of Health Sciences University of Manitoba Winnipeg Canada Gustave Roussy Cancer Campus Villejuif France Faculty of Medicine Universitě Paris-Saclay Kremlin-Bicêtre France INSERM U1030 Villejuif France Department of Cardiology Renmin Hospital of Wuhan University Wuhan Hubei China Institute for Medical Informatics Statistics and Documentation Medical University Graz Graz Austria Center for Diagnostics and Research in

Cancer is a major and still increasing cause of death in *** cancer cells have a fundamentally different metabolic profile from that of normal *** shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis,termed Warburg effect,has long been recognized as a paradigmatic hallmark of cancer,supporting the increased biosynthetic demands of tumor *** we show that deletion of apoptosis-inducing factor (AIF) in a KrasG12D-driven mouse lung cancer model resulted in a marked survival advantage,with delayed tumor onset and decreased malignant ***,Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor ***,although Aif-deficient cells exhibited a metabolic Warburg profile,this bioenergetic change resulted in a growth disadvantage of KrasG12D-driven as well as Kras wild-type lung cancer ***-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial,but abrogated apoptotic function) in Aif-knockout KrasG12D mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type *** patients with non-small cell lung cancer,high AIF expression was associated with poor *** data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.

关键词： Mechanisms of disease Non-small-cell lung cancer

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COMBINATION OF AN APELIN ANTAGONIST AND AN ANGIOGENESIS INHIBITOR FOR THE TREATMENT OF CANCER

COMBINATION OF AN APELIN ANTAGONIST AND AN ANGIOGENESIS INHI...

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作者： PENNINGER, Josef uribesalgo, iris

标准号: EP3228630(A1)

The field of the present invention is the field of anti-angiogenic cancer therapy. Efforts are needed to reduce or overcome resistance of cancer to anti-angiogenic therapies, such as therapies based on the receptor tyrosine kinase (RTK) inhibitor sunitinib. It is hence an object of the present invention to provide an agent that can be combined with an anti-angiogenic therapy in order to reduce or overcome resistance to the anti-angiogenic therapy. The present invention thus relates to a pharmaceutical composition or set comprising an apelin antagonist and/or apelin receptor antagonist, and an angiogenesis inhibitor. The angiogenesis inhibitor is an RTK inhibitor, preferably sunitinib. The apelin antagonist can be an anti-apelin antibody. The apelin receptor antagonist can be an apelin peptide analogue or an anti-apelin-receptor antibody. Furthermore, methods of cancer treatment, especially breast or lung cancer treatment, based on an apelin antagonist and/or apelin receptor antagonist, and an angiogenesis inhibitor are disclosed.

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COMBINATION OF AN APELIN ANTAGONIST AND AN ANGIOGENESIS INHIBITOR FOR THE TREATMENT OF CANCER

COMBINATION OF AN APELIN ANTAGONIST AND AN ANGIOGENESIS INHI...

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作者： PENNINGER, Josef uribesalgo, iris

标准号: WO2017174758(A1)

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The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate

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CELL REPORTS 2016年第7期15卷 1481-1492页

作者： Tortola, Luigi Nitsch, Roberto Bertrand, Mathieu J. M. Kogler, Melanie Redouane, Younes Kozieradzki, Ivona uribesalgo, iris Fennell, Lilian M. Daugaard, Mads Klug, Helene Wirnsberger, Gerald Wimmer, Reiner Perlot, Thomas Sarao, Renu Rao, Shuan Hanada, Toshikatsu Takahashi, Nozomi Kernbauer, Elisabeth Demiroez, Duygu Superti-Furga, Giulio Decker, Thomas Pichler, Andrea Ikeda, Fumiyo Kroemer, Guido Vandenabeele, Peter Sorensen, Poul H. Penninger, Josef M. Austrian Acad Sci IMBA Inst Mol Biotechnol A-1030 Vienna Austria AstraZeneca IMED Biotech Unit Discovery Sci Pepparedsleden 1 S-43183 Molndal Sweden VIB Inflammat Res Ctr Technol Pk 927 B-9052 Zwijnaarde Ghent Belgium Univ Ghent Dept Biomed Mol Biol Technol Pk 927 B-9052 Zwijnaarde Belgium Vancouver Prostate Ctr Vancouver BC V6H 3Z6 Canada Univ British Columbia Dept Urol Sci Vancouver BC V5Z 1M9 Canada Max Planck Inst Immunobiol & Epigenet Dept Epigenet Stubeweg 51 D-79108 Freiburg Germany Univ Vienna Max F Perutz Labs Dr Bohrgasse 9-4 A-1030 Vienna Austria Ctr Mol Med CEMM A-1060 Vienna Austria INSERM U848 39 Rue Camille Desmoulins F-94805 Villejuif France Inst Gustave Roussy Metabol & Cell Biol Platforms 39 Rue Camille Desmoulins F-94805 Villejuif France Ctr Rech Cordeliers 15 Rue Ecole Med F-75006 Paris France Hop Europeen Georges Pompidou AP HP Pole Biol F-75015 Paris France Univ Paris 05 Sorbonne Paris Cite F-75006 Paris France Univ British Columbia BC Canc Res Ctr Dept Mol Oncol Vancouver BC V5Z 1L3 Canada

The HECT domain E3 ligase HACE1 has been identified as a tumor suppressor in multiple cancers. Here, we report that HACE1 is a central gatekeeper of TNFR1-induced cell fate. Genetic inactivation of HACE1 inhibits TNF-stimulated NF-kappa B activation and TNFR1-NF-kappa B-dependent pathogen clearance in vivo. Moreover, TNF-induced apoptosis was impaired in hace1 mutant cells and knockout mice in vivo. Mechanistically, HACE1 is essential for the ubiquitylation of the adaptor protein TRAF2 and formation of the apoptotic caspase-8 effector complex. Intriguingly, loss of HACE1 does not impair TNFR1-mediated necroptotic cell fate via RIP1 and RIP3 kinases. Loss of HACE1 predisposes animals to colonic inflammation and carcinogenesis in vivo, which is markedly alleviated by genetic inactivation of RIP3 kinase and TNFR1. Thus, HACE1 controls TNF-elicited cell fate decisions and exerts tumor suppressor and anti-inflammatory activities via a TNFR1-RIP3 kinase-necroptosis pathway.

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The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate (vol 15, pg 1481, 2016)

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CELL REPORTS 2016年第12期16卷 3414-3414页

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The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells

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NATURE 2014年第7493期507卷 508-+页

作者： Paolino, Magdalena Choidas, Axel Wallner, Stephanie Pranjic, Blanka uribesalgo, iris Loeser, Stefanie Jamieson, Amanda M. Langdon, Wallace Y. Ikeda, Fumiyo Fededa, Juan Pablo Cronin, Shane J. Nitsch, Roberto Schultz-Fademrecht, Carsten Eickhoff, Jan Menninger, Sascha Unger, Anke Torka, Robert Gruber, Thomas Hinterleitner, Reinhard Baier, Gottfried Wolf, Dominik Ullrich, Axel Klebl, Bert M. Penninger, Josef M. Austrian Acad Sci Inst Mol Biotechnol IMBA A-1030 Vienna Austria Lead Discovery Ctr GmbH D-44227 Dortmund Germany Med Univ Innsbruck A-6020 Innsbruck Austria Brown Univ Dept Microbiol & Immunol Providence RI 02912 USA Univ Western Australia Sch Pathol & Lab Med Perth WA 6009 Australia Max Planck Inst Biochem Dept Mol Biol D-82152 Martinsried Germany Univ Hosp Bonn D-53127 Bonn Germany

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy(1). New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies(2). Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology(3). This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.

关键词： Immunosurveillance

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From oncogene to tumor suppressor The dual role of Myc in leukemia

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CELL CYCLE 2012年第9期11卷 1757-1764页

作者： uribesalgo, iris Aznar Benitah, Salvador Di Croce, Luciano CRG Barcelona Spain UPF Barcelona Spain ICREA Barcelona Spain

The transcription factor c-Myc strongly stimulates cell proliferation but also regulates apoptosis, senescence, cell competition and cell differentiation, and its elevated activity is a hallmark for human tumorigenesis. c-Myc induces transcription by forming heterodimers with Max and then directly binding DNA at E-box sequences. Conversely, transcription repression depends primarily on the inhibitory interaction of c-Myc/Max with Miz-1 at DNA initiator elements. We recently described a distinct mechanism of c-Myc gene regulation, in which c-Myc interacts with the retinoic acid receptor alpha (RAR alpha) and is recruited to RAR DNA binding sequences (RAREs). In leukemia cells, this c-Myc/RAR alpha complex functions either as an activator or a repressor of RAR alpha-dependent targets through a phosphorylation switch. Unphosphorylated c-Myc interacts with RAR alpha to repress the expression of RAR targets required for differentiation, thereby aggravating leukemia malignancy. However, if c-Myc is phosphorylated by the kinase Pak2, the c-Myc/RAR alpha complex activates transcription of those same genes to stimulate differentiation, thus reducing tumor burden. Here, we discuss the role of c-Myc in balancing proliferation and differentiation and how modulating this previously unidentified c-Myc activity might provide alternative therapies against leukemia and possibly other types of tumors.

关键词： c-Myc transcription max gene regulation chromatin retinoic acid RAR leukemia

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Polycomb Regulates NF-κB Signaling in Cancer through miRNA

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CANCER CELL 2012年第1期21卷 5-7页

作者： uribesalgo, iris Ballare, Cecilia Di Croce, Luciano CRG Barcelona 08003 Spain UPF Barcelona 08003 Spain ICREA Barcelona 08010 Spain

The mechanisms leading to the constitutive activation of NF-kappa B in cancers and the pathways upstream and downstream of this activation are not fully understood. In this issue of Cancer Cell, Yamagishi et al. demonstrate that Polycomb-mediated silencing of miR-31 is implicated in the aberrant activation of NF-kappa B signaling in tumors.

关键词： CANCER genetics POLYCOMB group proteins NF-kappa B (DNA-binding protein) CELLULAR signal transduction CANCER cells GENETIC regulation

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Dynamics of epigenetic modifications in leukemia

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BRIEFINGS IN FUNCTIONAL GENOMICS 2011年第1期10卷 18-29页

作者： uribesalgo, iris Di Croce, Luciano ICREA Barcelona 08003 Spain CRG Barcelona Spain

Chromatin modifications at both histones and DNA are critical for regulating gene expression. Mis-regulation of such epigenetic marks can lead to pathological states;indeed, cancer affecting the hematopoietic system is frequently linked to epigenetic abnormalities. Here, we discuss the different types of modifications and their general impact on transcription, as well as the polycomb group of proteins, which effect transcriptional repression and are often mis-regulated. Further, we discuss how chromosomal translocations leading to fusion proteins can aberrantly regulate gene transcription through chromatin modifications within the hematopoietic system. PML-RARa, AML1-ETO and MLL-fusions are examples of fusion proteins that mis-regulate epigenetic modifications (either directly or indirectly), which can lead to acute myeloblastic leukemia (AML). An in-depth understanding of the mechanisms behind the mis-regulation of epigenetic modifications that lead to the development and progression of AMLs could be critical for designing effective treatments.

关键词： chromatin epigenetics transcription leukemia polycom

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