Journal Article

Tumour exosome integrins determine organotropic metastasis

Weiss, Joshua M., Narendran, Aru, Di Giannatale, Angela, Batra, Surinder K., Jørgen Labori, Knut, Jain, Maneesh, Brady, Mary S., Davies, Alexander E., Uryu, Kunihiro, Minn, Andy J., King, Tari, Hashimoto, Ayako, Rajasekhar, Vinagolu K., Pantel, Klaus, Shen, Tang-Long, Kaur, Sukhwinder, Peinado, Hector, de Sousa, Maria, Muller, Volkmar, Zhang, Tuo, Grandgenett, Paul M., Bromberg, Jacqueline, Costa-Silva, Bruno, Bissell, Mina J., Schwartz, Gary K., Kramer, Kimberly, Matei, Irina, Dumont-Cole, Vanessa D., Ararso, Yonathan, Lyden, David, Healey, John H., Garcia, Benjamin A., Rodrigues, Goncalo, Kang, Yibin, Soplop, Nadine, Ghajar, Cyrus M., Hoshino, Ayuko, Hollingsworth, Michael A., Wexler, Leonard H., Ceder, Sophia, Hernandez, Jonathan, Fodstad, Oystein, Jarnagin, William R., Kohsaka, Shinji, Kure, Elin H., Pharmer, Lindsay, Williams, Caitlin, Singh, Swarnima, Sandstrom, Per, Tesic Mark, Milica, Molina, Henrik, Mallya, Kavita, Zhang, Haiying, Bojmar, Linda

2015

Overview

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α 6 β 4 and α 6 β 1 were associated with lung metastasis, while exosomal integrin α v β 5 was linked to liver metastasis. Targeting the integrins α 6 β 4 and α v β 5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis. Exosomes originating from lung-, liver- and brain-tropic tumour cells are preferentially incorporated by specific resident cells of the target organs, thus preparing the site for metastasis; the expression of distinct combinations of exosomal integrin proteins determines the exosomal targeting to each of the three organs, and blocking these integrins reduces organotropic exosome uptake by the target organs, thereby reducing the likelihood of organotropic metastasis. Metastasis site selection involves tumour exosomes How do cancer cells choose the next organ to target? David Lyden and colleagues show that extracellular vesicles (exosomes) that originate from tumour cells can preferentially fuse with specific resident cells of the target organs — lung, liver and brain — to prepare the site of metastasis. At a molecular level, expression of distinct combinations of integrin proteins on exosomes seems to mediate their targeting to one of the three organs. By blocking these integrins, the authors could reduce the uptake of the associated exosomes by the target organs and so the likelihood of metastasis. Moreover, the exosomal integrins could be used to predict organ-specific metastasis in cancer patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 60 APPLIED LIFE SCIENCES / 631/67/322 / 631/67/327 / 631/80/304 / Animals / BASIC BIOLOGICAL SCIENCES / Biomarkers - metabolism / Brain - cytology / Brain - metabolism / Breast cancer / Cancer metastasis / cancer microenvironment / Cell Line, Tumor / Chemokines / Complications and side effects / Development and progression / Endothelial Cells - cytology / Endothelial Cells - metabolism / Epithelial Cells - cytology / Epithelial Cells - metabolism / Exosomes - metabolism / Female / Fibroblasts / Fibroblasts - cytology / Fibroblasts - metabolism / Genes, src / Health aspects / Humanities and Social Sciences / Humans / Integrin alpha6beta1 - metabolism / Integrin alpha6beta4 - antagonists & inhibitors / Integrin alpha6beta4 - metabolism / Integrin beta Chains - metabolism / Integrin beta4 - metabolism / Integrins / Integrins - antagonists & inhibitors / Integrins - metabolism / Kupffer Cells - cytology / Kupffer Cells - metabolism / Liver / Liver - cytology / Liver - metabolism / Lung - cytology / Lung - metabolism / mechanisms of disease / Melanoma / Metastasis / Mice / Mice, Inbred C57BL / Microscopy / multidisciplinary / Neoplasm Metastasis - pathology / Neoplasm Metastasis - prevention & control / Organ Specificity / Organelles / Phosphorylation / Receptors, Vitronectin - antagonists & inhibitors / Receptors, Vitronectin - metabolism / S100 Proteins - genetics / Science / Studies / Tropism / Tumors