Early dissemination seeds metastasis in breast cancer

• Published in: Nature (London) Vol. 540; no. 7634; pp. 552 - 558
• Main Authors: Hosseini, Hedayatollah, Obradović, Milan M. S., Hoffmann, Martin, Harper, Kathryn L., Sosa, Maria Soledad, Werner-Klein, Melanie, Nanduri, Lahiri Kanth, Werno, Christian, Ehrl, Carolin, Maneck, Matthias, Patwary, Nina, Haunschild, Gundula, Gužvić, Miodrag, Reimelt, Christian, Grauvogl, Michael, Eichner, Norbert, Weber, Florian, Hartkopf, Andreas D., Taran, Florin-Andrei, Brucker, Sara Y., Fehm, Tanja, Rack, Brigitte, Buchholz, Stefan, Spang, Rainer, Meister, Gunter, Aguirre-Ghiso, Julio A., Klein, Christoph A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.12.2016; Nature Publishing Group
• Subjects: 631/67/1347; 631/67/322; Breast cancer; Cancer metastasis; Cell growth; Gene expression; Humanities and Social Sciences; Lesions; Metastasis; multidisciplinary; Observations; Physiological aspects; Rodents; Science; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature20785

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. Two related papers show that cells disseminated from malignant lesions at early time points during tumorigenesis can contribute to metastases at distant organs and provide insights into the molecular basis of dissemination. A potential mechanism for metastases The origin of metastases in cancer remains an open question. In a pair of linked papers, Christoph Klein, Julio Aguirre-Ghiso and colleagues now show in mouse models that cells disseminated from tumours early in tumorigenesis can contribute to metastases at distant organs at such early time points. Both papers also provide insights into the molecular basis of dissemination, which may be useful as targets to prevent metastasis.