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Signal Transduction and Functional Imaging

Identification and Characterization of Cancer Cells That Initiate Metastases to the Brain and Other Organs

Anna. S. Berghoff, Yunxiang Liao, Matthia A. Karreman, Ayseguel Ilhan-Mutlu, Katharina Gunkel, Martin R. Sprick, Christian Eisen, Tobias Kessler, Matthias Osswald, Susanne Wünsche, Manuel Feinauer, Brunhilde Gril, Frederic Marmé, Laura L. Michel, Zuszanna Bago-Horvath, Felix Sahm, Natalia Becker, Michael O. Breckwoldt, Gergely Solecki, Miriam Gömmel, Lulu Huang, Petra Rübmann, Carina M. Thome, Miriam Ratliff, Andreas Trumpp, Patricia S. Steeg, Matthias Preusser, Wolfgang Wick and Frank Winkler
Anna. S. Berghoff
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
3Department of Medicine 1, Medical University of Vienna, Vienna, Austria.
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Yunxiang Liao
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Matthia A. Karreman
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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  • ORCID record for Matthia A. Karreman
Ayseguel Ilhan-Mutlu
3Department of Medicine 1, Medical University of Vienna, Vienna, Austria.
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Katharina Gunkel
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Martin R. Sprick
4Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
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  • ORCID record for Martin R. Sprick
Christian Eisen
4Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
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Tobias Kessler
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Matthias Osswald
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Susanne Wünsche
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Manuel Feinauer
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Brunhilde Gril
5Women’s Malignancies Branch, Laboratory of Pathology, Center for Cancer Research, Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland.
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Frederic Marmé
6Department of Gynecology and Obstetrics and National Center for Tumor Diseases, University Hospital, Heidelberg, Germany.
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  • ORCID record for Frederic Marmé
Laura L. Michel
6Department of Gynecology and Obstetrics and National Center for Tumor Diseases, University Hospital, Heidelberg, Germany.
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Zuszanna Bago-Horvath
7Department of Pathology, Medical University of Vienna, Vienna, Austria.
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Felix Sahm
8Department of Neuropathology, Institute of Pathology, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.
9Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Natalia Becker
10Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Michael O. Breckwoldt
11Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany.
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Gergely Solecki
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Miriam Gömmel
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Lulu Huang
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Petra Rübmann
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Carina M. Thome
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Miriam Ratliff
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Andreas Trumpp
4Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
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Patricia S. Steeg
5Women’s Malignancies Branch, Laboratory of Pathology, Center for Cancer Research, Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland.
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Matthias Preusser
3Department of Medicine 1, Medical University of Vienna, Vienna, Austria.
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Wolfgang Wick
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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Frank Winkler
1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
2Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
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  • For correspondence: frank.winkler@med.uni-heidelberg.de
DOI: 10.1158/1541-7786.MCR-20-0863
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Abstract

Specific biological properties of those circulating cancer cells that are the origin of brain metastases (BM) are not well understood. Here, single circulating breast cancer cells were fate-tracked during all steps of the brain metastatic cascade in mice after intracardial injection over weeks. A novel in vivo two-photon microscopy methodology was developed that allowed to determine the specific cellular and molecular features of breast cancer cells that homed in the brain, extravasated, and successfully established a brain macrometastasis. Those BM-initiating breast cancer cells (BMIC) were mainly originating from a slow-cycling subpopulation that included only 16% to 20% of all circulating cancer cells. BMICs showed enrichment of various markers of cellular stemness. As a proof of principle for the principal usefulness of this approach, expression profiling of BMICs versus non-BMICs was performed, which revealed upregulation of NDRG1 in the slow-cycling BMIC subpopulation in one BM model. Here, BM development was completely suppressed when NDRG1 expression was downregulated. In accordance, in primary human breast cancer, NDRG1 expression was heterogeneous, and high NDRG1 expression was associated with shorter metastasis-free survival. In conclusion, our data identify temporary slow-cycling breast cancer cells as the dominant source of brain and other metastases and demonstrates that this can lead to better understanding of BMIC-relevant pathways, including potential new approaches to prevent BM in patients.

Implications: Cancer cells responsible for successful brain metastasis outgrowth are slow cycling and harbor stemness features. The molecular characteristics of these metastasis-initiating cells can be studied using intravital microscopy technology.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;XX:XX–XX

  • Received October 2, 2020.
  • Revision received November 8, 2020.
  • Accepted December 9, 2020.
  • Published first December 22, 2020.
  • ©2020 American Association for Cancer Research.
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This OnlineFirst version was published on January 29, 2021
doi: 10.1158/1541-7786.MCR-20-0863

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Identification and Characterization of Cancer Cells That Initiate Metastases to the Brain and Other Organs
Anna. S. Berghoff, Yunxiang Liao, Matthia A. Karreman, Ayseguel Ilhan-Mutlu, Katharina Gunkel, Martin R. Sprick, Christian Eisen, Tobias Kessler, Matthias Osswald, Susanne Wünsche, Manuel Feinauer, Brunhilde Gril, Frederic Marmé, Laura L. Michel, Zuszanna Bago-Horvath, Felix Sahm, Natalia Becker, Michael O. Breckwoldt, Gergely Solecki, Miriam Gömmel, Lulu Huang, Petra Rübmann, Carina M. Thome, Miriam Ratliff, Andreas Trumpp, Patricia S. Steeg, Matthias Preusser, Wolfgang Wick and Frank Winkler
Mol Cancer Res January 29 2021 DOI: 10.1158/1541-7786.MCR-20-0863

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Identification and Characterization of Cancer Cells That Initiate Metastases to the Brain and Other Organs
Anna. S. Berghoff, Yunxiang Liao, Matthia A. Karreman, Ayseguel Ilhan-Mutlu, Katharina Gunkel, Martin R. Sprick, Christian Eisen, Tobias Kessler, Matthias Osswald, Susanne Wünsche, Manuel Feinauer, Brunhilde Gril, Frederic Marmé, Laura L. Michel, Zuszanna Bago-Horvath, Felix Sahm, Natalia Becker, Michael O. Breckwoldt, Gergely Solecki, Miriam Gömmel, Lulu Huang, Petra Rübmann, Carina M. Thome, Miriam Ratliff, Andreas Trumpp, Patricia S. Steeg, Matthias Preusser, Wolfgang Wick and Frank Winkler
Mol Cancer Res January 29 2021 DOI: 10.1158/1541-7786.MCR-20-0863
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Molecular Cancer Research
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