Oncogenic KIT-containing exosomes increasegastrointestinal stromal tumor cell invasion

During tumor development, constant interplay occurs betweentumor cells and surrounding stromal cells. We report evidence thatgastrointestinal stromal tumor (GIST) cells invade the interstitialstroma through the release of the oncogenic protein tyrosinekinase (KIT)-containing exosomes, which triggers the pheno-typic conversion of progenitor smooth muscle cells to tumor-promoting cells. These recipient cells display morphologic changesand acquire tumor-associated phenotypes, including enhancedadhesion to extracellular matrix proteins, activation of intracel-lular pathways downstream of KIT, expression of InterstitialCell of Cajal-like markers, and release of various matrix metal-loproteinases (MMPs), particularly MMP1. This report shows stimulation of MMP1 production by stromal cells via uptake of tumor-derived exosomes, which leads to tumor cell invasion. Exosomesderived from GIST patients but not healthy donors show enhanced MMP1 secretion by smooth muscle cells and tumor cellinvasion, whereas selective blocking of exosome-mediated MMP1secretion decreases tumor invasiveness. Our study indicates thatexosome release and subsequent MMP1 induction creates a positive feedback mechanism established between tumor and stromalcells that drives GIST development and offers unique insights forpotential therapeutic strategies to block GIST progression andmetastatic spread.