title: Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A.
abstract: Despite the approval of numerous molecular targeted drugs, long-term antiproliferative efficacy is rarely achieved and therapy resistance remains a central obstacle of cancer care. Combined inhibition of multiple cancer-driving pathways promises to improve antiproliferative efficacy. HIF-1 is a driver of gastric cancer and considered to be an attractive target for therapy. We noted that gastric cancer cells are able to functionally compensate the stable loss of HIF-1α. Via transcriptomics we identified a group of upregulated genes in HIF-1α-deficient cells and hypothesized that these genes confer survival upon HIF-1α loss. Strikingly, simultaneous knock-down of HIF-1α and Annexin A1 (ANXA1), one of the identified genes, resulted in complete cessation of proliferation. Using stable isotope-resolved metabolomics, oxidative and reductive glutamine metabolism was found to be significantly impaired in HIF-1α/ANXA1-deficient cells, potentially explaining the proliferation defect. In summary, we present a conceptually novel application of stable gene inactivation enabling in-depth deconstruction of resistance mechanisms. In theory, this experimental approach is applicable to any cancer-driving gene or pathway and promises to identify various new targets for combination therapies.
authors.affiliation: Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité, Berlin, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Rohwer
authors.affiliation: Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Bindel
authors.affiliation: Max-Planck-Institut for Molecular Genetics, Berlin, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Grimm
authors.affiliation: Duke-NUS Graduate Medical School, Singapore.
authors.forename: Suling J
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: GROW School of Oncology and Developmental Biology and Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wappler
authors.affiliation: Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Integrative Research Institute (IRI) for The Life Sciences and Institute for Theoretical Biology, Humboldt-Universität Berlin, Berlin, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Klinger
authors.affiliation: Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Integrative Research Institute (IRI) for The Life Sciences and Institute for Theoretical Biology, Humboldt-Universität Berlin, Berlin, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Blüthgen
authors.affiliation: Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University, Marburg, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Du Bois
authors.affiliation: Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University, Marburg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schmeck
authors.affiliation: Max-Planck-Institut for Molecular Genetics, Berlin, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Amsterdam, The Netherlands.
authors.forename: Marjo
authors.initials: M
authors.lastname: de Graauw
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge, United Kingdom.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Goncalves
authors.affiliation: Joint Research Centre for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, Faculty of Medicine, Aachen, Germany.
authors.forename: Julio
authors.initials: J
authors.lastname: Saez-Rodriguez
authors.affiliation: Duke-NUS Graduate Medical School, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: GROW School of Oncology and Developmental Biology and Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Heike I
authors.initials: HI
authors.lastname: Grabsch
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prigione
authors.affiliation: Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kempa
authors.affiliation: Molecular Tumor Biology, Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Aachen, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Cramer
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D013274:Stomach Neoplasms / Q000378:metabolism*
chemical_list: D017305:Annexin A1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering
keywords: Annexin A1; HIF-1; cancer metabolism; cancer therapy; induced essentiality