Direct investigation of the early cellular changes induced by metastatic cells within the surrounding tissue remains a challenge. Here we present a system in which metastatic cancer cells release a cell-penetrating fluorescent protein, which is taken up by neighbouring cells and enables spatial identification of the local metastatic cellular environment. Using this system, tissue cells with low representation in the metastatic niche can be identified and characterized within the bulk tissue. To highlight its potential, we applied this strategy to study the cellular environment of metastatic breast cancer cells in the lung. We report the presence of cancer-associated parenchymal cells, which exhibit stem-cell-like features, expression of lung progenitor markers, multi-lineage differentiation potential and self-renewal activity. In ex vivo assays, lung epithelial cells acquire a cancer-associated parenchymal-cell-like phenotype when co-cultured with cancer cells and support their growth. These results highlight the potential of this method as a platform for new discoveries.
Bibliographical noteWe thank E. Sahai, P. Scaffidi (The Francis Crick Institute) and V. Sanz-Moreno (Barts Cancer Institute) for scientific discussions, critical reading of the manuscript and sharing cell lines and mouse strains; M. Izquierdo (CSIC, Madrid) for sharing the CD63–GFP plasmid; E. Nye and the pathologists G. Stamp and E. Herbert from the Experimental Histopathology Unit at the Francis Crick Institute for histological processing and analysis support; J. Bee from the Biological Resources Unit at the Francis Crick Institute for technical support with mice and mouse tissues; R. Goldstone and A. Edwards from the Advanced Sequencing Facility at the Francis Crick Institute for technical support; M. Llorian-Sopena from the Bioinformatics and Biostatistics Unit at the Francis Crick Institute for helping with the RNA sequencing analysis; the Flow Cytometry Unit at the Francis Crick Institute, particularly S. Purewal and J. Cerveira, for invaluable technical help; the Cell Services Unit at the Francis Crick Institute; C. Moore (The Francis Crick Institute) for intra-tracheal injections; and I. Pshenichnaya, P. Humphreys, S. McCallum and Cambridge Stem Cell Institute core facilities for technical assistance. We acknowledge support from the FLI Core Facility Proteomics, which is a member of the Leibniz Association and is financially supported by the Federal Government of Germany and the State of Thuringia. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001112), the UK Medical Research Council (FC001112), and the Wellcome Trust (FC001112) and the European Research Council grant (ERC CoG-H2020-725492); and by the Wellcome Trust—MRC Stem Cell Institute, which receives funding from the Sir Henry Dale Fellowship from Wellcome, the Royal Society (107633/Z/15/Z) and the European Research Council Starting Grant (679411).
Author Correction: Metastatic-niche labelling reveals parenchymal cells with stem features (Nature, (2019), 572, 7771, (603-608), 10.1038/s41586-019-1487-6)
Luigi Ombrato, Emma Nolan, Ivana Kurelac, Antranik Mavousian, Victoria Louise Bridgeman, Ivonne Heinze, Probir Chakravarty, Stuart Horswell, Estela Gonzalez-Gualda, Giulia Matacchione, Anne Weston, Joanna Kirkpatrick, Ehab Husain, Valerie Speirs, Lucy Collinson, Alessandro Ori, Joo Hyeon Lee, Ilaria Malanchi, 2019, vol. 575, issue 7784, p. E8. Nature http://dx.doi.org/10.1038/s41586-019-1697-y
- Cancer microenvironment
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- School of Medicine, Medical Sciences & Nutrition, Molecular and Cellular Function
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Chair in Molecular Oncology
- Institute of Medical Sciences
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cancer Centre
Andrea Holme (Manager)Iain Fraser Cytometry Centre
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