Early dissemination seeds metastasis in breast cancer

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 Maneck, Nina Patwary, Gundula Haunschild, Miodrag Gužvić, Christian Reimelt, Michael Grauvogl, Norbert Eichner, Florian Weber, Andreas D. Hartkopf, Florin-Andrei Taran, Sara Y. Brucker, Tanja Fehm, Brigitte Rack, Stefan Buchholz, Rainer Spang, Gunter Meister, Julio A. Aguirre-Ghiso and Christoph A. Klein ()
Additional contact information
Hedayatollah Hosseini: Experimental Medicine and Therapy Research, University of Regensburg
Milan M. S. Obradović: Experimental Medicine and Therapy Research, University of Regensburg
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
Melanie Werner-Klein: Institute of Immunology, University of Regensburg
Lahiri Kanth Nanduri: Experimental Medicine and Therapy Research, University of Regensburg
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

Nature, 2016, vol. 540, issue 7634, 552-558

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature20785

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