Tumour exosome integrins determine organotropic metastasis

Abstract

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.

Involvement of serum‐derived exosomes of elderly patients with bone loss in failure of bone remodeling via alteration of exosomal bone‐related proteins

“…Furthermore, our analysis showed that proteins implicated in the processes of integrin‐mediated adhesion and mechanosensation were downregulated in the SDEs of patients with osteoporosis. Exosome binding by recipient cells is likely to be determined by a repertoire of integrins, which dictate exosome adhesion to specific cell types and ECM molecules (Hoshino et al., 2015). Among the DEPs of SDEs of osteoporosis patients, the β 1 and β 3 integrins and CD34 were representatives of the downregulated proteins.…”

“…Hoshino et al. (2015) demonstrated that, in addition to adhesive properties, exosomal integrin uptake can activate SRC in specific resident cells. SRC is an upstream signaling partner of ERK and regulates SMAD nuclear translation through activation of osterix and results in osteoblastic bone mineralization (Choi et al., 2015).…”

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

“…The cellular origin of an EV can guide its surface-expressed proteins, intrinsic targeting properties, and target cell tropism. For example, Hoshino et al reported that tumour cell-derived exosomes display different integrins depending on the tumour origin, and these proteins mediate tumour metastasis to specific organ sites; exosomes expressing ITGαvβ5 specifically bind to Kupffer cells and thus mediate liver tropism, whereas exosomal ITGα6β4 and ITGα6β1 bind lung-resident fibroblasts and epithelial cells to govern lung tropism [84]. Another study showed that tetraspanin-associated receptors on exosomal membranes can play an important role in target cell selection, as exosomes containing tetraspanin–integrin complexes (span8–integrin α4 complexes) could target CD54-expressing endothelial and pancreatic cells [85].…”

Precipitation with polyethylene glycol followed by washing and pelleting by ultracentrifugation enriches extracellular vesicles from tissue culture supernatants in small and large scales

“…tetraspanins and flotillins) as well as coding and non-coding RNAs (including microRNAs), and different types of lipids [1,3–5]. The molecular organisation of their surface provides a kind of address code allowing them to selectively interact with specific target cells [6,7]. Thus, depending on their origin and their cargo, EVs can exert specific functions.…”