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Early dissemination seeds metastasis in breast cancer

Author

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  • Hedayatollah Hosseini

    (Experimental Medicine and Therapy Research, University of Regensburg)

  • Milan M. S. Obradović

    (Experimental Medicine and Therapy Research, University of Regensburg
    †Present addresses: Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland (M.M.S.O.); Department of Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York 10029, USA (M.S.S.); Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany (L.K.N.).)

  • Martin Hoffmann

    (Project group ‘Personalized Tumour Therapy’, Fraunhofer Institute for Toxicology und Experimental Medicine)

  • Kathryn L. Harper

    (Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai)

  • Maria Soledad Sosa

    (Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai
    †Present addresses: Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland (M.M.S.O.); Department of Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York 10029, USA (M.S.S.); Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany (L.K.N.).)

  • Melanie Werner-Klein

    (Institute of Immunology, University of Regensburg)

  • Lahiri Kanth Nanduri

    (Experimental Medicine and Therapy Research, University of Regensburg
    †Present addresses: Tumor Heterogeneity, Metastasis and Resistance, Department of Biomedicine, University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland (M.M.S.O.); Department of Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York 10029, USA (M.S.S.); Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany (L.K.N.).)

  • Christian Werno

    (Project group ‘Personalized Tumour Therapy’, Fraunhofer Institute for Toxicology und Experimental Medicine)

  • Carolin Ehrl

    (Experimental Medicine and Therapy Research, University of Regensburg)

  • Matthias Maneck

    (Experimental Medicine and Therapy Research, University of Regensburg)

  • Nina Patwary

    (Experimental Medicine and Therapy Research, University of Regensburg)

  • Gundula Haunschild

    (Experimental Medicine and Therapy Research, University of Regensburg)

  • Miodrag Gužvić

    (Experimental Medicine and Therapy Research, University of Regensburg)

  • Christian Reimelt

    (Experimental Medicine and Therapy Research, University of Regensburg)

  • Michael Grauvogl

    (Institute of Functional Genomics, University of Regensburg)

  • Norbert Eichner

    (Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg)

  • Florian Weber

    (Institute of Pathology, University of Regensburg)

  • Andreas D. Hartkopf

    (University of Tübingen)

  • Florin-Andrei Taran

    (University of Tübingen)

  • Sara Y. Brucker

    (University of Tübingen)

  • Tanja Fehm

    (University of Düsseldorf)

  • Brigitte Rack

    (University Munich)

  • Stefan Buchholz

    (University Medical Center Regensburg)

  • Rainer Spang

    (Institute of Functional Genomics, University of Regensburg)

  • Gunter Meister

    (Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg)

  • Julio A. Aguirre-Ghiso

    (Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai)

  • Christoph A. Klein

    (Experimental Medicine and Therapy Research, University of Regensburg
    Project group ‘Personalized Tumour Therapy’, Fraunhofer Institute for Toxicology und Experimental Medicine)

Abstract

Accumulating data suggest that metastatic dissemination often occurs early during tumour formation, but the mechanisms of early metastatic spread have not yet been addressed. Here, by studying metastasis in a HER2-driven mouse breast cancer model, we show that progesterone-induced signalling triggers migration of cancer cells from early lesions shortly after HER2 activation, but promotes proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by increased HER2 expression and tumour-cell density involving microRNA-mediated progesterone receptor downregulation, and was reversible. Cells from early, low-density lesions displayed more stemness features, migrated more and founded more metastases than cells from dense, advanced tumours. Notably, we found that at least 80% of metastases were derived from early disseminated cancer cells. Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination.

Suggested Citation

  • Hedayatollah Hosseini & Milan M. S. Obradović & Martin Hoffmann & Kathryn L. Harper & Maria Soledad Sosa & Melanie Werner-Klein & Lahiri Kanth Nanduri & Christian Werno & Carolin Ehrl & Matthias Manec, 2016. "Early dissemination seeds metastasis in breast cancer," Nature, Nature, vol. 540(7634), pages 552-558, December.
    • Handle: RePEc:nat:nature:v:540:y:2016:i:7634:d:10.1038_nature20785
    DOI: 10.1038/nature20785
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    Cited by:

    1. Qiuchen Guo & Milos Spasic & Adam G. Maynard & Gregory J. Goreczny & Amanuel Bizuayehu & Jessica F. Olive & Peter Galen & Sandra S. McAllister, 2022. "Clonal barcoding with qPCR detection enables live cell functional analyses for cancer research," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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