Research Papers:

Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A

Nadine Rohwer, Fabian Bindel, Christina Grimm, Suling J. Lin, Jessica Wappler, Bertram Klinger, Nils Blüthgen, Ilona Du Bois, Bernd Schmeck, Hans Lehrach, Marjo de Graauw, Emanuel Goncalves, Julio Saez-Rodriguez, Patrick Tan, Heike I. Grabsch, Alessandro Prigione, Stefan Kempa and Thorsten Cramer _

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Oncotarget. 2016; 7:6693-6710. https://doi.org/10.18632/oncotarget.6793

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Nadine Rohwer1,2,3,*, Fabian Bindel4,*, Christina Grimm5, Suling J. Lin6, Jessica Wappler13, Bertram Klinger7,8, Nils Blüthgen7,8, Ilona Du Bois9, Bernd Schmeck9, Hans Lehrach5, Marjo de Graauw10, Emanuel Goncalves11, Julio Saez-Rodriguez12, Patrick Tan6, Heike I. Grabsch13, Alessandro Prigione14, Stefan Kempa4,#, Thorsten Cramer15,#

1Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité, Berlin, Germany

2German Cancer Consortium (DKTK), Heidelberg, Germany

3German Cancer Research Center (DKFZ), Heidelberg, Germany

4Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

5Max-Planck-Institut for Molecular Genetics, Berlin, Germany

6Duke-NUS Graduate Medical School, Singapore

7Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany

8Integrative Research Institute (IRI) for the Life Sciences and Institute for Theoretical Biology, Humboldt-Universität Berlin, Berlin, Germany

9Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University, Marburg, Germany

10Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Amsterdam, The Netherlands

11European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge, United Kingdom

12Joint Research Centre for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, Faculty of Medicine, Aachen, Germany

13GROW School of Oncology and Developmental Biology and Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands

14Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

15Molecular Tumor Biology, Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Aachen, Germany

*These authors contributed equally to this work

#These authors jointly directed this work

Correspondence to:

Thorsten Cramer, e-mail: [email protected]

Stefan Kempa, e-mail: [email protected]

Keywords: cancer therapy, Annexin A1, cancer metabolism, HIF-1, induced essentiality

Received: June 29, 2015     Accepted: December 08, 2015     Published: December 29, 2015


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.

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