Cancer-associated cells release citrate to support tumour metastatic progression-Reference-Cited by-同舟云学术

Cancer-associated cells release citrate to support tumour metastatic progression

Published:2021-03-23 Issue:6 Volume:4 Page:e202000903
ISSN:2575-1077
Container-title:Life Science Alliance
language:en
Short-container-title:Life Sci. Alliance

Author:

Drexler Konstantin¹,Schmidt Katharina M²,Jordan Katrin²,Federlin Marianne³,Milenkovic Vladimir M⁴,Liebisch Gerhard⁵^ORCID,Artati Anna⁶,Schmidl Christian⁷^ORCID,Madej Gregor⁸,Tokarz Janina⁶,Cecil Alexander⁶,Jagla Wolfgang⁹,Haerteis Silke¹⁰,Aung Thiha¹⁰¹¹,Wagner Christine²,Kolodziejczyk Maria²,Heinke Stefanie²,Stanton Evan H²,Schwertner Barbara¹,Riegel Dania⁷,Wetzel Christian H⁴^ORCID,Buchalla Wolfgang³,Proescholdt Martin¹²,Klein Christoph A¹³,Berneburg Mark¹^ORCID,Schlitt Hans J²^ORCID,Brabletz Thomas¹⁴,Ziegler Christine⁸,Parkinson Eric K¹⁵^ORCID,Gaumann Andreas⁹,Geissler Edward K²,Adamski Jerzy⁶¹⁶¹⁷,Haferkamp Sebastian¹^ORCID,Mycielska Maria E²^ORCID

Affiliation:

1. Department of Dermatology, University Medical Centre, Regensburg, Germany

2. Department of Surgery, University Medical Center, Regensburg, Germany

3. Department of Conservative Dentistry and Periodontology, University Medical Center, Regensburg, Germany

4. Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany

5. Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany

6. Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany

7. Regensburg Center for Interventional Immunology, Regensburg, Germany

8. Department of Structural Biology, Institute of Biophysics and Physical Biochemistry, University of Regensburg, Regensburg, Germany

9. Institute of Pathology, Kaufbeuren-Ravensburg, Kaufbeuren, Germany

10. Institute for Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany

11. Center of Plastic, Aesthetic, Hand and Reconstructive Surgery, University of Regensburg, Regensburg, Germany

12. Department of Neurosurgery, University Hospital Regensburg, Regensburg, Germany

13. Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany

14. Department of Experimental Medicine 1, Friedrich-Alexander-University Erlangen, Erlangen, Germany

15. Centre for Immunobiology and Regenerative Medicine, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK

16. Lehrstuhl für Experimentelle Genetik, Technische Universität München, Munich, Germany

17. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Abstract

Citrate is important for lipid synthesis and epigenetic regulation in addition to ATP production. We have previously reported that cancer cells import extracellular citrate via the pmCiC transporter to support their metabolism. Here, we show for the first time that citrate is supplied to cancer by cancer-associated stroma (CAS) and also that citrate synthesis and release is one of the latter’s major metabolic tasks. Citrate release from CAS is controlled by cancer cells through cross-cellular communication. The availability of citrate from CAS regulated the cytokine profile, metabolism and features of cellular invasion. Moreover, citrate released by CAS is involved in inducing cancer progression especially enhancing invasiveness and organ colonisation. In line with the in vitro observations, we show that depriving cancer cells of citrate using gluconate, a specific inhibitor of pmCiC, significantly reduced the growth and metastatic spread of human pancreatic cancer cells in vivo and muted stromal activation and angiogenesis. We conclude that citrate is supplied to tumour cells by CAS and citrate uptake plays a significant role in cancer metastatic progression.

Funder

DFG grant

Else-Kröner-Fresenius-Stiftung grant

ReFoRmC

DFG

Else-Kröner-Fresenius-Stiftung

Publisher

Life Science Alliance, LLC

Subject

Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology

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