Abstract

Hypoxia is a poor-prognosis microenvironmental hallmark of solid tumours, but it is unclear how it influences the fate of disseminated tumour cells (DTCs) in target organs. Here we report that hypoxic HNSCC and breast primary tumour microenvironments displayed upregulation of key dormancy (NR2F1, DEC2, p27) and hypoxia (GLUT1, HIF1α) genes. Analysis of solitary DTCs in PDX and transgenic mice revealed that post-hypoxic DTCs were frequently NR2F1hi/DEC2hi/p27hi/TGFβ2hi and dormant. NR2F1 and HIF1α were required for p27 induction in post-hypoxic dormant DTCs, but these DTCs did not display GLUT1hi expression. Post-hypoxic DTCs evaded chemotherapy and, unlike ER breast cancer cells, post-hypoxic ER+ breast cancer cells were more prone to enter NR2F1-dependent dormancy. We propose that primary tumour hypoxic microenvironments give rise to a subpopulation of dormant DTCs that evade therapy. These post-hypoxic dormant DTCs may be the source of disease relapse and poor prognosis associated with hypoxia.

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Acknowledgements

We thank the Aguirre-Ghiso, Condeelis and Castracane laboratories for useful discussions. We thank N. Linde and M. S. Sosa for help and advice during initial phases of this study on the detection of TGFβ2 and NR2F1. This study was supported by: the Samuel Waxman Cancer Research Foundation Tumor Dormancy Program to J.A.A.-G.; the NIH/NCI TMEN U54CA163131 to J.Condeelis, P.J.K., J.Castracane and J.A.A.-G.; NIH/NCI grants CA109182 and CA191430 to J.A.A.-G.; DoD-BCRP Breakthrough Award (BC132674) to J.A.A.-G. and J.Condeelis; NCI Cancer Center P30 grant CA196521 to J.A.A.-G.; the TCI Young Scientist Cancer Research Award JJR Fund and NCI K22CA196750 grants to J.J.B.-C.; and the German Research Foundation (DFG) Fellowship (FL 865/1-1) and University Hospital Duesseldorf, Department of General and Visceral Surgery to G.F. Special optical devices were constructed and validated in the Gruss Lippoer Biophotonic Center and Integrated Imaging Program at Einstein. All imaging was performed in the Microscopy CORE at the Icahn School of Medicine at Mount Sinai. We thank N. Tzavaras (Microscopy CORE) for his technical help.

Author information

Author notes

    • Georg Fluegen
    •  & Alvaro Avivar-Valderas

    These authors contributed equally to this work.

    • Alvaro Avivar-Valderas

    Present address: AstraZeneca, iMED Oncology, Hodgkin Building, Chesterford Research Campus, Saffron Walden, Cambridge CB10 1XL, UK.

Affiliations

  1. Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA

    • Georg Fluegen
    • , Alvaro Avivar-Valderas
    • , Ana Rita Nobre
    • , Veronica Calvo
    • , Julie F. Cheung
    • , Jose Javier Bravo-Cordero
    •  & Julio A. Aguirre-Ghiso
  2. Department of General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital of the Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany

    • Georg Fluegen
  3. Department of Anatomy and Structural Biology, Gruss Lipper Biophotonics Center, Integrated Imaging Program, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA

    • Yarong Wang
    • , David Entenberg
    • , Vladislav Verkhusha
    •  & John Condeelis
  4. Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, New York 12203, USA

    • Michael R. Padgen
    • , James K. Williams
    •  & James Castracane
  5. Department of Cell and Regenerative Biology, Laboratory of Molecular Biology, University of Wisconsin-Madison, 1525 Linden Drive, Madison, Wisconsin 53706, USA

    • Patricia J. Keely

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Contributions

Conceptualization: J.A.A.-G., J.Condeelis, P.J.K., A.A.-V., G.F.; methodology: J.Condeelis, J.Castracane, D.E., A.R.N., J.F.C., V.C.; investigation: G.F., A.A.-V., A.R.N., J.F.C., V.C.; resources: Y.W., M.R.P., J.K.W., V.V., J.F.C., J.J.B.-C.; writing: G.F., J.A.A.-G.; visualization: G.F., A.A.-V.; funding acquisition: J.Condeelis, J.Castracane, P.J.K., J.A.A.-G., J.J.B.-C., G.F.; supervision: J.A.A.-G., J.Condeelis.

Competing interests

J.A.A.-G. receives funding from E. Lilly and co. J.Condeelis is a consultant for, and has equity in MetaStat, Inc.; J.Condeelis is also a consultant for Deciphera Pharmaceuticals.

Corresponding authors

Correspondence to John Condeelis or Julio A. Aguirre-Ghiso.

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https://doi.org/10.1038/ncb3465

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