Exosomes released by metabotropic glutamate receptor 1 (GRM1) expressing melanoma cells increase cell migration and invasiveness

Abstract

Exosomes are naturally occurring membrane-bound nanovesicles generated constitutively and released by various cell types, and often in higher quantities by tumor cells. Exosomes may facilitate communication between the primary tumor and its local microenvironment, supporting cell invasion and other early events in metastasis. A neuronal receptor, metabotropic glutamate receptor 1 (GRM1), when ectopically expressed in melanocytes, induces in vitro melanocytic transformation and spontaneous malignant melanoma development in vivo in a transgenic mouse model. Our earlier studies showed that genetic modulation in GRM1 expression by siRNA or disruption of GRM1-mediated glutamate signaling interfere with downstream effectors resulting in a decrease in both cell proliferation in vitro and tumor progression in vivo. In this study, we sought to determine whether exosome formation might play a role in GRM1 mediated melanoma development and progression. To test this, we utilized in vitro cultured cells in which GRM1 expression and function could be modulated by pharmacological and genetic means and determined effects on exosome production. We also tested the effects of exosomes from GRM1 expressing melanoma cells on growth, migration and invasion of GRM1 negative cells. Our results show that although GRM1 expression has no influence on exosome quantity, exosomes produced by GRM1-positive cells modulate the ability of the recipient cell to migrate, invade and exhibit anchorage-independent cell growth.

Concurrent Targeting of Glutaminolysis and Metabotropic Glutamate Receptor 1 (GRM1) Reduces Glutamate Bioavailability in GRM1+ Melanoma

“…Suppressive effects of riluzole on GRM1 þ melanoma cell proliferation were reported earlier (17,39,40). Here, the consequences of including both CB-839 and riluzole on cell growth of two GRM1-expressing human melanoma cell lines were investigated.…”

Small extracellular vesicles convey the stress-induced adaptive responses of melanoma cells

“…They share many antigens with vascular endothelial cells (vasculogenic mimicry) which enables them to survive in the circulation, and increases their migration and invasion capacity as well. Furthermore, melanoma-derived extracellular vesicles also have a crucial role in the rapid tumour progression 8–12 . They are capable to induce a tumour-favourable phenotype in the EV-recipient cells in the TME 13 and the metastatic sites 14,15 .…”

Overcoming Immune Evasion in Melanoma

“…Our lab demonstrated that inhibition of mGluR1 expression or function by genetic or pharmacological inhibitors in melanoma cells, did not modulate the number of exosomes released, but rather reduced the functions of the exosomes on the recipient cells in cell migration, invasion, and anchorage-independent growth, perhaps through cargo sorting into exosomes [357].…”