@article{c399579b420a478ea23ee9d0d9d30cd1,
title = "Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models",
abstract = " Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca 2+ -dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction and Ly6C + CCR2 + monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells or Ccr2 in host cells blunts the pro-metastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy.",
author = "Ioanna Keklikoglou and Chiara Cianciaruso and Esra G{\"u}{\c c} and Squadrito, {Mario Leonardo} and Spring, {Laura M.} and Simon Tazzyman and Lore Lambein and Amanda Poissonnier and Ferraro, {Gino B.} and Caroline Baer and Antonino Cassar{\'a} and Alan Guichard and Iruela-Arispe, {M. Luisa} and Lewis, {Claire E.} and Coussens, {Lisa M.} and Aditya Bardia and Jain, {Rakesh K.} and Pollard, {Jeffrey W.} and {De Palma}, Michele",
note = "Funding Information: L.M.S. reports consulting fees from Novartis. L.M.C. is a paid consultant for Cell Signaling Technologies, received reagent support from Plexxikon and NanoString Technologies and is a member of the Scientific Advisory Boards of Syndax Pharmaceuticals, Carisma Therapeutics and Verseau Therapeutics. A.B. reports consulting fees from Genentech/Roche, Immunomedics, Novartis, Pfizer, Merck, Radius Health, Spectrum Pharma and Taiho Pharma and received a research grant from Biothernostics. R.K.J. received honoraria from Amgen and consultancy fees from Merck, Ophthotech, Pfizer, SPARC, SynDevRx, and XTuit, owns equity in Enlight, Ophthotech, SynDevRx and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. M.D.P. reports honoraria from Merck and Sanofi/Regeneron Pharmaceuticals, received sponsored research grants from Hoffmann La-Roche, MedImmune and Deciphera Pharmaceuticals and serves on the Scientific Advisory Boards of Deciphera Pharmaceuticals and Genenta. The other authors declare no competing interests. Neither materials nor funding from the above organizations were used in this study. Funding Information: We thank C. Rmili-Wyser, A. Bellotti, B. Torchia, D. Laoui (M.D.P.{\textquoteright}s laboratory) and M. Duquette (R.K.J.{\textquoteright}s laboratory) for help with some experiments; T. Kitamura (University of Edinburgh) for advice on lung colonization assays and for providing E0771-LG and E0771-LG:Fl cells and H.G. Augustin (DKFZ) for critical comments on the manuscript. The EPFL core facilities of flow cytometry (FCCF), histology (HCF) and bioimaging/ optics platform (BIOp) are acknowledged for skilled technical assistance; R. Hamelin and M. Moniatte of the proteomics facility (PCF, EPFL) for performing LC–MS/MS on EVs; T.J. Chico for providing access to zebrafish lines in the aquarium at the University Sheffield and R. Klemke for the kind gift of CFP-MDA-MB-435 cells. This work was primarily funded by grants from the Swiss Cancer League (grant no. KFS-3007-08-2012), Swiss National Science Foundation (grant no. SNF 31003A-165963) and European Research Council (grant no. ERC EVOLVE-72505) to M.D.P. L.M.S. was supported by NIH grant no. KL2 TR001100. C.E.L. acknowledges support from Cancer Research UK (grant no. C11712/A13028), Yorkshire Cancer Research (grant no. S382) and Breast Cancer Now (grant nos 2016MayPR746 and 2016NovPCC003). M.L.I.-A. was supported by NIH (NCI 1R01CA197943). L.M.C. acknowledges support from a DOD BCRP Era of Hope Scholar Expansion Award (grant no. W81XWH-08-PRMRP-IIRA), Susan B Komen Foundation (grant no. KG110560) and Breast Cancer Research Foundation. A.B. was supported by Susan B Komen Foundation (grant no. CCR15224703). R.K.J. acknowledges support from the Ludwig Center at Harvard, National Foundation for Cancer Research and NCI (grant no. R35CA197743). J.W.P. was supported by the Wellcome Trust (grant no. 101067/Z/13/Z) and MRC (grant no. MR/N022556/1). Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = feb,
day = "1",
doi = "10.1038/s41556-018-0256-3",
language = "English (US)",
volume = "21",
pages = "190--202",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "2",
}