Impaired Cellular Cholesterol Homeostasis Decreases Tumor-Derived Exosome Load And Modulates Malignant Transformation...

Tumor-derived exosomes (TDEs) play a crucial role in horizontally transferring oncogenic information from tumors to other sites. Cellular cholesterol homeostasis has emerged as a significant factor influencing exosomal biogenesis and cellular release. In this study, we employed U18666A to induce cholesterol accumulation within the late endosomes of MDA-MB231 cells. We assessed the capacity of exosomes derived from U18666A-treated and untreated cells to initiate malignant transformation in HEK293 cells. Exosomes were isolated and characterized from both untreated and U18666A-treated MDA-MB231 cells, and HEK293 cells. The impact of exosomes derived from untreated MDA-MB231 cells (referred to as UCE) and U18666A-treated MDA-MB231 cells (referred to as UTCE) to induce transformation on HEK293 cells was investigated. Exosomes derived from MDA-MB231 cells induced proliferation, migration, malignant transformation, and epithelial-mesenchymal transition (EMT) process in HEK293 cells. Treatment with U18666A resulted in cholesterol accumulation within late endosomes, consequently markedly reversing the EMT process in MDA-MB231 cells. This treatment diminished the content of Tumor-derived exosomes released by the cancer cells, rendering them less oncogenic. This reduction in oncogenic potential was evident as they lost the ability to induce malignant transformation in recipient HEK293 cells. Modulating cholesterol homeostasis and disrupting the supply of cholesterol to aggressive cancer cells emerges as an appealing strategy to restrain the release of Tumor-derived exosomes and subsequently mitigate their contributory role in driving cancer progression and metastasis.