Glutamine deprivation alters the origin and function of cancer cell exosomes

Abstract

Exosomes are secreted extracellular vesicles carrying diverse molecular cargos, which can modulate recipient cell behaviour. They are thought to derive from intraluminal vesicles formed in late endosomal multivesicular bodies ( MVB s). An alternate exosome formation mechanism, which is conserved from fly to human, is described here, with exosomes carrying unique cargos, including the GTP ase Rab11, generated in Rab11‐positive recycling endosomal MVB s. Release of Rab11‐positive exosomes from cancer cells is increased relative to late endosomal exosomes by reducing growth regulatory Akt/mechanistic Target of Rapamycin Complex 1 ( mTORC 1) signalling or depleting the key metabolic substrate glutamine, which diverts membrane flux through recycling endosomes. Vesicles produced under these conditions promote tumour cell proliferation and turnover and modulate blood vessel networks in xenograft mouse models in vivo . Their growth‐promoting activity, which is also observed in vitro , is Rab11a‐dependent, involves ERK ‐ MAPK ‐signalling and is inhibited by antibodies against amphiregulin, an EGFR ligand concentrated on these vesicles. Therefore, glutamine depletion or mTORC 1 inhibition stimulates release from Rab11a compartments of exosomes with pro‐tumorigenic functions, which we propose promote stress‐induced tumour adaptation.

The forces driving cancer extracellular vesicle secretion

“…Tumour-derived EVs support broad oncogenic processes such as angiogenesis [10] , immune modulation [ 11 , 12 ], and metastasis [13] , [14] , [15] , [16] , [17] . Compared to non-malignant cells, cancer cells have been found to increase the amount of EVs produced [18] , [19] , [20] , shift the subtype of EVs that they secrete [21] , and/or alter the cargo molecules that are selected for expulsion [ 2 , 22 , 23 ]. Of note, education by tumor cells can also affect the secretion rate and the content of EVs derived from platelets [24] , as well as noncancer cells in the TME [8] , but in this review we chose to focus on EV secretion from cancer cells only.…”

“…Besides this tumor intrinsic link between metabolism and EV secretion, extrinsic changes in cancer cell metabolism can also influence the production of cancer EVs. A recent publication reported that the depletion of glutamine from the TME causes a shift in the subtype of cancer EVs that are released; switching from late-endosomal CD63-positive exosomes towards RAB11a-positive exosomes that originate from recycling endosomes and promote tumor vascularization [21] .…”

“…In hepatic stellate cells mTORC1 signaling enhances EV secretion [79] , while in mouse embryonic fibroblasts mTORC1 signaling inhibits Rab27a-dependent exosome secretion [80] . In various cancer cell lines, mTORC1 inhibition with rapamycin or via glutamine deprivation induce the secretion of protumorigenic RAB11-positive exosomes [21] .…”

Autophagy and Exosomes Relationship in Cancer: Friends or Foes?

“…Very recently, using Drosophila model and human cell lines, Fan et al (2020) have found that glutamine depletion induces secretion of exosomes carrying exclusive cargos created in Rab11−positive recycling endosomal MVBs. Interestingly, the release of exosomes from glutamine depleted HCT116 cells stimulate angiogenesis and enhances tumor cell proliferation.…”

Extracellular vesicles: eat glutamine and spit acidic bubbles

“…A recent article by Fan et al () clearly illustrates the power of such cell biology approaches. In this work, the authors now demonstrate an additional complexity of EVs formed intracellularly in endosomes, by showing that exosomes can contain the usual late endosomal compartments such as the tetraspanin CD63 and the Rab7 intracellular trafficking GTPase, but also molecular actors of earlier endosomal compartment such as Rab11a that decorates recycling endosomes.…”