Tumour exosome integrins determine organotropic metastasis

TY - JOUR

T1 - Tumour exosome integrins determine organotropic metastasis

AU - Hoshino, Ayuko

AU - Costa-Silva, Bruno

AU - Shen, Tang-Long

AU - Rodrigues, Goncalo

AU - Hashimoto, Ayako

AU - Tesic Mark, Milica

AU - Molina, Henrik

AU - Kohsaka, Shinji

AU - Di Giannatale, Angela

AU - Ceder, Sophia

AU - Singh, Swarnima

AU - Williams, Caitlin

AU - Soplop, Nadine

AU - Uryu, Kunihiro

AU - Pharmer, Lindsay

AU - King, Tari

AU - Bojmar, Linda

AU - Davies, Alexander E

AU - Ararso, Yonathan

AU - Zhang, Tuo

AU - Zhang, Haiying

AU - Hernandez, Jonathan

AU - Weiss, Joshua M

AU - Dumont-Cole, Vanessa D

AU - Kramer, Kimberly

AU - Wexler, Leonard H

AU - Narendran, Aru

AU - Schwartz, Gary K

AU - Healey, John H

AU - Sandstrom, Per

AU - Jørgen Labori, Knut

AU - Kure, Elin H

AU - Grandgenett, Paul M

AU - Hollingsworth, Michael A

AU - de Sousa, Maria

AU - Kaur, Sukhwinder

AU - Jain, Maneesh

AU - Mallya, Kavita

AU - Batra, Surinder K

AU - Jarnagin, William R

AU - Brady, Mary S

AU - Fodstad, Oystein

AU - Muller, Volkmar

AU - Pantel, Klaus

AU - Minn, Andy J

AU - Bissell, Mina J

AU - Garcia, Benjamin A

AU - Kang, Yibin

AU - Rajasekhar, Vinagolu K

AU - Ghajar, Cyrus M

AU - Matei, Irina

AU - Peinado, Hector

AU - Bromberg, Jacqueline

AU - Lyden, David

PY - 2015/11/19

Y1 - 2015/11/19

N2 - 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 α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 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.

AB - 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 α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 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.

U2 - 10.1038/nature15756

DO - 10.1038/nature15756

M3 - SCORING: Journal article

C2 - 26524530

VL - 527

SP - 329

EP - 335

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7578

ER -